Treprostinil derivative compounds and methods of using same

ABSTRACT

Compounds represented by formulae I, II, III, and IV including pro-drugs for treprostinil and prostacyclin analogs. Uses include treatment of pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH). The structures of the compounds can be adapted to the particular application for a suitable treatment dosage. Transdermal applications can be used.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of U.S.application Ser. No. 14/153,498 filed on Jan. 13, 2014, which claimspriority to U.S. Provisional Application No. 61/751,608 filed on Jan.11, 2013, each of which is incorporated herein by reference in itsentirety for all purposes.

BACKGROUND

Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) isa disease which can result in death and is characterized by increasedpulmonary artery pressure and pulmonary vascular resistance. A needexists for better compounds and methods for treating PH and PAH. See,for example, US Patent Publication No. 2013/0274261. Many valuablepharmacologically active compounds, including some of interest withrespect to PH and PAH, cannot be effectively administered orally forvarious reasons and are generally administered via intravenous orintramuscular routes. These routes of administration generally requireintervention by a physician or other health care professional, and canentail considerable discomfort as well as potential local trauma to thepatient. One example of such a compound is treprostinil and derivativesthereof, which has been used in the treatment of PH and PAH. See, forexample, WO 2005/007081. Treprostinil (herein also called Compound A)has the following structure:

Treprostinil can exist as a salt, such as a sodium salt.

Accordingly, there is a clinical need in providing treprostinil byimproved formulations and methods, e.g., either orally or transdermally.More particularly, there is a need for a safe and effective method forincreasing the systemic availability of treprostinil via administrationof treprostinil or derivatives (including prodrugs) or analogs thereof.

The application of transdermal drug delivery technology to theadministration of a wide variety of drugs has been proposed and varioussystems for accomplishing this are disclosed in numerous technicaljournals and patents. U.S. Pat. Nos. 3,598,122; 4,144,317; 4,201,211;4,262,003; and 4,379,454, all of which are incorporated herein byreference, are representative of various transdermal drug deliverysystems of the prior art, which systems have the ability of deliveringcontrolled amounts of drugs to patients for extended periods of timeranging in duration from several hours to several days. None of theabove patents describes a transdermal delivery system which is intendedto deliver treprostinil or its derivatives.

SUMMARY

Embodiments described herein include compounds, compositions, anddevices, as well as methods of making and methods of using the same.

One embodiment provides a compound represented by Formula (I)

wherein, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁,R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are independently H or deuterium;

-   Z is —OH, —OR₁₁, —N(R₁₁)R₁₂, —SR₁₁, or P₁;-   R₁₁ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,    haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl,    substituted cycloheteroalkyl, alkylcycloalkyl, substituted    alkylcycloalkyl, alkylcycloheteroalkyl, substituted    alkylcycloheteroalkyl, aryl, substituted aryl, alkylaryl,    substituted alkylaryl, heteroaryl, substituted heteroaryl,    alkylheteroaryl, or substituted alkylheteroaryl;-   R₁₂ is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,    alkylcycloheteroalkyl, aryl, or heteroaryl;-   P₁ is selected from the group consisting of:

wherein,

-   m is 1, 2, 3, or 4;-   R₁₄ and R₁₅ are independently in each occurrence selected from the    group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl,    haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl,    arylalkyl, heteroarylalkyl, substituted aryl, substituted    heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl;-   R₁₄ and R₁₅ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring optionally incorporating one    or two ring heteroatoms chosen from N, O, or S, which is    unsubstituted or substituted with 1, 2, or 3 substituents    independently selected from the group consisting of halo, methyl,    and methoxy;-   R₁₈ and R₁₉ are independently in each occurrence selected from the    group consisting of hydrogen and alkyl, wherein the alkyl is    unsubstituted or substituted with I substituent selected from the    group consisting of halo, hydroxy, alkoxy, amino, thio, methylthio,    —C(O)OH, —C(O)O-(alkyl), —CONH₂, aryl, and heteroaryl, wherein the    aryl or heteroaryl are unsubstituted or substituted from the group    consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, and    haloalkoxy;-   R₁₄ and R₁₈ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₄ and R₁₉ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₅ and R₁₈ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₅ and R₁₉ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   and, R₁ and R₂ are independently H or P₂, wherein at least one of R₁    and R₂ is P₂, wherein-   P₂ is selected from the group consisting of:

wherein,

-   m is 1, 2, 3, or 4;-   R₁₄ and R₁₅ are as defined above;-   R₁₄ and R₁₅ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring optionally incorporating one    or two ring heteroatoms chosen from N, O, or S, which is    unsubstituted or substituted with 1, 2, or 3 substituents    independently selected from the group consisting of halo, methyl and    methoxy;-   R₁₆ and R₁₇ are independently in each occurrence H or alkyl;-   R₁₆ and R₁₇ taken together with the atoms to which they attach    optionally form a 3- to 6-membered ring;-   R₁₈ and R₁₉ are as defined above;-   R₁₄ and R₁₈ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₄ and R₁₉ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   wherein Formula I includes enantiomers, pharmaceutically acceptable    salts, solvates and polymorphs of the compounds of Formula I.

In another embodiment, the parameters of Formula I are defined asfollows:

-   R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂,    R₃₃, R₃₄, R₃₅, and R₃₆ are independently H or deuterium;-   Z is —OR₁₁, —N(R₁₁)R₁₂, —SR₁₁, or P₁;-   R₁₁ is branched alkyl, haloalkyl, halocycloalkyl, heteroalkyl,    substituted heteroalkyl, cycloheteroalkyl, substituted    cycloheteroalkyl, bicycloalkyl, alkylcycloalkyl, substituted    alkylcycloalkyl, alkylcycloheteroalkyl, substituted    alkylcycloheteroalkyl, alkylaryl, substituted alkylaryl, heteroaryl,    substituted heteroaryl, alkylheteroaryl, or substituted    alkylheteroaryl;-   R₁₂ is H, branched alkyl, haloalkyl, heteroalkyl, cycloheteroalkyl,    alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl;-   P₁ is selected from the group consisting of:

wherein,

-   m is 1, 2, 3, or 4;-   R₁₄ and R₁₅ are independently in each occurrence selected from the    group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl,    haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl,    arylalkyl, heteroarylalkyl, substituted aryl, substituted    heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl;-   R₁₄ and R₁₅ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring optionally incorporating one    or two ring heteroatoms chosen from N, O, or S, which is    unsubstituted or substituted with 1, 2, or 3 substituents    independently selected from the group consisting of halo, methyl,    and methoxy;-   R₁₈ and R₁₉ are independently in each occurrence selected from the    group consisting of hydrogen and alkyl, wherein the alkyl is    unsubstituted or substituted with 1 substituent selected from the    group consisting of halo, hydroxy, alkoxy, amino, thio, methylthio,    —C(O)OH, —C(O)O-(alkyl), —CONH₂, aryl, and heteroaryl, wherein the    aryl or heteroaryl are unsubstituted or substituted from the group    consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, and    haloalkoxy;-   R₁₄ and R₁₈ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₄ and R₁₉ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₅ and R₁₈ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₅ and R₁9 taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   and, R₁ and R₂ are independently H or P₂, wherein-   P₂ is selected from the group consisting of:

wherein,

-   m is 1, 2, 3, or 4;-   R₁₄ and R₁₅ are as defined above;-   R₁₄ and R₁₅ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring optionally incorporating one    or two ring heteroatoms chosen from N, O, or S, which is    unsubstituted or substituted with 1, 2, or 3 substituents    independently selected from the group consisting of halo, methyl and    methoxy;-   R₁₆ and R₁₇ are independently in each occurrence H or alkyl;-   R₁₆ and R₁₇ taken together with the atoms to which they attach    optionally form a 3- to 6-membered ring;-   R₁₈ and R₁₉ are as defined above;-   R₁₄ and R₁₈ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₄ and R₁₉ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   wherein Formula I includes enantiomers, pharmaceutically acceptable    salts, solvates and polymorphs of the compounds of Formula I.

In another embodiment, provided is a compound represented by Formula II:

wherein,

-   R₂ is selected from the group consisting of H and P₂;-   R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂,    R₃₃, R₃₄, R₃₅, and R₃₆ are independently selected from the group    consisting of H and deuterium;-   L₁ is selected from the group consisting of —O-alkylene-C(O)—,    —O-alkylene-OC(O)—, or a bond; wherein-   P₂ is selected from the group consisting of:

wherein,

-   m is 1, 2, 3, or 4;-   R₁₄ and R₁₅ are as defined above;-   R₁₄ and R₁₅ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring optionally incorporating one    or two ring heteroatoms chosen from N, O, or S, which is    unsubstituted or substituted with 1, 2, or 3 substituents    independently selected from the group consisting of halo, methyl and    methoxy;-   R₁₆ and R₁₇ are independently in each occurrence H or alkyl;-   R₁₆ and R₁₇ taken together with the atoms to which they attach    optionally form a 3- to 6-membered ring;-   R₁₈ and R₁₉ are as defined above;-   R₁₄ and R₁₈ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₄ and R₁₉ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   wherein Formula H includes enantiomers, pharmaceutically acceptable    salts, solvates and polymorphs of the compounds of Formula II.

In another embodiment, a compound is represented by Formula III:

wherein L₂ is selected from the group consisting of —CH₂—, —CHMe-,—C(Me)₁- and the following:

wherein,

-   m is 1, 2, 3, or 4;-   X is NR₁₄ or O;-   R₁₄ is selected from the group consisting of H, alkyl, cycloalkyl,    alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl,    heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl,    substituted heteroaryl, substituted arylalkyl, and substituted    heteroarylalkyl;-   R₁₆ and R₁₇ are independently in each occurrence H or alkyl;-   R₁₆ and R₁₇ taken together with the atoms to which they attach    optionally form a 3- to 6-membered ring; and-   R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂,    R₃₃, R₃₄, R₃₅, and R₃₆ are independently selected from the group    consisting of H and deuterium;-   wherein Z is —OH, —OR₁₁, —N(R₁₁)R₁₂, —SR₁₁, or P₁;-   R₁₁ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,    haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl,    substituted cycloheteroalkyl, alkylcycloalkyl, substituted    alkylcycloalkyl, alkylcycloheteroalkyl, substituted    alkylcycloheteroalkyl, aryl, substituted aryl, alkylaryl,    substituted alkylaryl, heteroaryl, substituted heteroaryl,    alkylheteroaryl, or substituted alkylheteroaryl;-   R₁₂ is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,    alkylcycloheteroalkyl, aryl, or heteroaryl;-   P₁ is selected from the group consisting of:

wherein,

-   m is 1, 2, 3, or 4;-   R₁₄ and R₁₅ are independently in each occurrence selected from the    group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl,    haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl,    arylalkyl, heteroarylalkyl, substituted aryl, substituted    heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl;-   R₁₄ and R₁₅ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring optionally incorporating one    or two ring heteroatoms chosen from N, O, or S, which is    unsubstituted or substituted with 1, 2, or 3 substituents    independently selected from the group consisting of halo, methyl,    and methoxy;-   R₁₈ and R₁₉ are independently in each occurrence selected from the    group consisting of hydrogen and alkyl, wherein the alkyl is    unsubstituted or substituted with 1 substituent selected from the    group consisting of halo, hydroxy, alkoxy, amino, thio, methylthio,    —C(O)OH, —C(O)O-(alkyl), —CONH₂, aryl, and heteroaryl, wherein the    aryl or heteroaryl is unsubstituted or substituted from the group    consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, and    haloalkoxy;-   R₁₄ and R₁₈ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₄ and R₁₉ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₅ and R₁₈ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₅ and R₁₉ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   wherein Formula III includes enantiomers, pharmaceutically    acceptable salts, solvates and polymorphs of the compounds of    Formula III.

Another embodiment provides a compound represented by Formula IV:

wherein,

-   R₁ is selected from the group consisting of H and P₂;-   R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂,    R₃₃, R₃₄, R₃₅, and R₃₆ are independently selected from the group    consisting of H and deuterium;-   L₁ is selected from the group consisting of —O-alkylene-C(O)—,    —O-alkylene-OC(O)—, or a bond; wherein-   P₂ is selected from the group consisting of:

wherein,

-   m is 1, 2, 3, or 4;-   R₁₄ and R₁₅ are independently in each occurrence selected from the    group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl,    haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl,    arylalkyl, heteroarylalkyl, substituted aryl, substituted    heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl;-   R₁₄ and R₁₅ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring optionally incorporating one    or two ring heteroatoms chosen from N, O, or S, which is    unsubstituted or substituted with 1, 2, or 3 substituents    independently selected from the group consisting of halo, methyl,    and methoxy;-   R₁₆ and R₁₇ are independently in each occurrence H or alkyl;-   R₁₆ and R₁₇ taken together with the atoms to which they attach    optionally form a 3- to 6-membered ring;-   R₁₈ and R₁₉ are independently in each occurrence selected from the    group consisting of hydrogen and alkyl, wherein the alkyl is    unsubstituted or substituted with 1 substituent selected from the    group consisting of halo, hydroxy, alkoxy, amino, thio, methylthio,    —C(O)OH, —C(O)O-(alkyl), —CONH₂, aryl, and heteroaryl, wherein the    aryl or heteroaryl is unsubstituted or substituted from the group    consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, and    haloalkoxy;-   R₁₄ and R₁₈ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₄ and R₁₉ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   wherein Formula IV includes enantiomers, pharmaceutically acceptable    salts, solvates and polymorphs of the compounds of Formula IV.

Compositions are also provided including compositions comprising atleast one compound according to Formula I, II, III or IV and at leastone other component. In one embodiment, the composition is formulatedfor transdermal delivery. In another embodiment, the composition isformulated for transdermal delivery with a patch. In one embodiment, thecomposition can further comprise at least one solvent. In oneembodiment, the amount of the compound according to Formula I, II, IIIor IV is adapted to provide a useful delivery profile for treatment of ahuman. In one embodiment, the treatment is carried out on a subject,such as a mammal, but the subject is not a human.

At least one advantage for at least one embodiment includes ability totailor the chemical structure of a pharmaceutically useful motif forparticular uses including treatment and prophylactic use against, forexample, PH and PAH. For example, the drug delivery profile can beadapted for a particular application.

At least one additional advantage for at least one embodiment includesability to use the compounds to provide better bioavailability includinguse in transdermal drug delivery applications.

DETAILED DESCRIPTION Introduction

Priority U.S. provisional application 61/751,608 filed Jan. 11, 2013 isincorporated herein by reference in its entirety for all purposesincluding the chemical formulae and claims, including Formula I, FormulaII, and Formula III, as well as Schemes 1-4, examples, and the tables ofstructures on pages 14-16.

Various prostacyclin analogs, including treprostinil, and methods fortheir use are known. For example, they can be used in promotingvasodilation, inhibiting platelet aggregation and thrombus formation,stimulating thrombolysis, inhibiting cell proliferation (includingvascular remodeling), providing cytoprotection, and preventingatherogenesis and inducing angiogenesis. Through theseprostacyclin-mimetic mechanisms, these compounds may be used in thetreatment of/for: pulmonary hypertension, ischemic diseases (e.g.,peripheral vascular disease, Raynaud's phenomenon, scleroderma,myocardial ischemia, ischemic stroke, renal insufficiency), heartfailure (including congestive heart failure), conditions requiringanticoagulation (e.g., post MI, post cardiac surgery), thromboticmicroangiopathy, extracorporeal circulation, central retinal veinocclusion, atherosclerosis, inflammatory diseases (e.g., COPD,psoriasis), hypertension (e.g., preeclampsia), reproduction andparturition, cancer or other conditions of unregulated cell growth,cell/tissue preservation, and other emerging therapeutic areas whereprostacyclin treatment appears to have a beneficial role. Thesecompounds may also demonstrate additive or synergistic benefit incombination with other cardiovascular agents (e.g., calcium channelblockers, phosphodiesterase inhibitors, endothelial antagonists, andantiplatelet agents).

Treprostinil is a chemically stable analog of prostacyclin. Althoughtreprostinil sodium (Remodulin®) is approved by the Food and DrugAdministration (FDA) for subcutaneous administration, treprostinil asthe free acid has an absolute oral bioavailability of less than 10% anda very short systemic half life due to significant metabolism.

Definitions

Herein, listings of chemical groups represented by multiple chemicalformulae are provided (e.g. P₁, P₂, L₁, and L₂). As used herein, thesegroup listings also describe any combination of subgroups of thechemical formulae in the group listing as well as any single formula inthe group listing.

The term “alkyl” refers to a monovalent saturated hydrocarbon group.C₁-C₈ alkyl is an alkyl having from 1 to 8 carbon atoms and includes,for example. C₁-C₃ alkyl, C₁-C₅ alkyl, and C₁-C₇ alkyl. An alkyl may belinear or branched. Examples of alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,isopentyl, neopentyl and n-hexyl.

The term “haloalkyl” refers to a monovalent saturated hydrocarbon groupattached to a one or more halogen atoms selected from Cl and F. Specificexamples include 2-fluoroethyl, 2.2-difluoroethyl, 2-fluoropropyl, and2,2-difluoropropyl.

The term “heteroalkyl” refers to a monovalent saturated hydrocarbongroup attached to one or more heteroatoms selected from O, N, and S.C₁-C₈ heteroalkyl is an alkyl having from 1 to 8 carbon atoms and one ormore heteroatoms selected from O, N and S, and includes, for example,C₁-C₃—OH, C₁-C₅—SH, and C₁-C₇—NH₂. It also includes C1—C2—O—C3—C4—OH,and C1—C2—NH—C3—C4—OH.

The term “cycloalkyl” refers to a monocyclic, bicyclic, or tricyclicmonovalent saturated hydrocarbon ring system. The term “C₃-C₁₄cycloalkyl” refers to a cycloalkyl wherein the number of ring carbonatoms is from 3 to 14. Examples of C₃-C₁₄ cycloalkyl include C₃-C₁₀cycloalkyl and C₃-C₆ cycloalkyl. Bicyclic and tricyclic ring systemsinclude fused, bridged and spirocyclic ring systems. More particularexamples of cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cis- and trans-decalynil,norbornyl, adamantyl, and spiro[4.5]decanyl.

The term “cycloheteroalkyl” or “heterocycloalkyl” refers to amonocyclic, bicyclic, or tricyclic monovalent saturated ring systemwherein from 1 to 4 ring atoms are heteroatoms independently selectedfrom the group consisting of O, N and S. The term “3- to 14-memberedcycloheteroalkyl” refers to a cycloheteroalkyl wherein the number ofring atoms is from 3 to 14. Examples of 3- to 14-memberedcycloheteroalkyl include 3- to 10-membered cycloheteroalkyl and 3- to6-membered cycloheteroalkyl. Bicyclic and tricyclic ring systems includefused, bridged and spirocyclic ring systems. More particular examples ofcycloheteroalkyl groups include azepanyl, azetidinyl, aziridinyl,imidazolidinyl, morpholinyl, oxazolidinyl, piperazinyl, piperidinyl,pyrazolidinyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl,thiomorpholinyl, and alpha-methyl-1,3-dioxol-2-onyl.

The term “alkylcycloalkyl” refers to a monocyclic, bicyclic, ortricyclic monovalent saturated hydrocarbon ring system linked to analkyl group. Particular examples include cyclopropylmethyl,cyclopropylethyl, and cyclohexylethyl.

The term “alkylheterocycloalkyl” or “alkylcycloheteroalkyl” refers to acycloheteroalkyl group attached to an alkyl group. Specific examplesinclude N-ethylmorpholine. N-ethylpiperidine, 4-ethylpiperidine,1-methyl-4-ethylpiperidine, and N-ethylpiperazine.

The term “aryl” refers to a monovalent aromatic carbocyclic ring system,which may be a monocyclic, fused bicyclic, or fused tricyclic ringsystem. The term “C₆-C₁₄ aryl” refers to an aryl having from 6 to 14ring carbon atoms. An example of C₆-C₁₄ aryl is C₆-C₁₀ aryl. Moreparticular examples of aryl groups include phenyl, naphthyl, anthracyl,and phenanthryl.

The term “heteroaryl” refers to an unsaturated aromatic heterocyclylradical. Examples of heteroaryl radicals include unsaturated 3- to6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, forexample, pyrrolyl, pyrrolinyl, imidazolyl, tetrazolyl, etc.; unsaturatedcondensed heterocyclyl groups containing 1 to 5 nitrogen atoms, forexample, indolyl, isoindolyl, benzimidazolyl, quinolyl, benzotrazolyl,tetrazolopyridazinyl, etc.; unsaturated 3- to 6-memberedheteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms, for example, oxazolyl, oxadiazolyl, etc.; unsaturatedcondensed heterocyclyl groups containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms; unsaturated 3- to 6-membered heteromonocyclic groupscontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example,thiazolyl, thiadiazolyl, etc.; and unsaturated condensed heterocyclylgroups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms.

The term “alkylaryl” refers to an aryl-substituted alkyl radical such asbenzyl, diphenylmethyl or phenylethyl.

The term “alkylheteroaryl” refers to a heteroaryl-substituted alkylradical such as imidazoylmethyl, thiazoylmethyl or pyridylethyl.

The terms described herein such as alkyl, haloalkyl, heteroalkyl,cycloalkyl, cycloheteroalkyl, alkylcycloalkyl, alkylheterocycloalkyl,aryl, heteroaryl, alkylaryl, and alkylheteroary, are understood to coveroptionally embodiments wherein they form rings. For example, optionallygroups such as R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, and R₁₉ can form rings withother R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, and R₁₉ groups.

The term “substituted” refers to the replacement of one or more hydrogenradicals in a given structure with the radical of a specifiedsubstituent including, but not limited to: halo, alkyl, alkenyl,alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl,alkylsulfonyl, alkylsulfonylalkyl, alkoxy, alkoxy, aryloxy,aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,aryloxycarbonyl, alkylhalo, amino, trifluoromethyl, cyano, nitro,alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, hydroxyl,alkyloxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl,acyl, carbonyl, carboxylic acid, sulfonic acid, phosphonic acid, aryl,heteroaryl, heterocyclic, and aliphatic. It is understood that thesubstituent may be further substituted within the normal limits of theskilled artisan. A moiety or group may be optionally substituted whichmeans the group may or may not have one or more substituents.

The term “compound” as used herein is also intended to include salts,solvates, hydrates and polymorphs thereof. The specific recitation of“salt”, “solvate”, “hydrate” or “polymorph” in certain aspects of theinvention described in this application shall not be interpreted as anintended omission of these forms in other aspects of the invention wherethe term “compound” is used without recitation of these other forms.

A salt of a compound of this invention is formed between an acid and abasic group of the compound, such as an amino functional group, or abase and an acidic group of the compound, such as a carboxyl functionalgroup. According to another preferred embodiment, the compound is apharmaceutically acceptable base addition salt or acid addition salt.

The term “pharmaceutically acceptable” refers to a component that is,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and other mammals without undue toxicity,irritation, allergic response and the like, and are commensurate with areasonable benefit/risk ratio. A “pharmaceutically acceptable salt”means any non-toxic salt that, upon administration to a recipient, iscapable of providing, either directly or indirectly, a compound or aprodrug of a compound of this invention. A “pharmaceutically acceptablecounterion” is an ionic portion of a salt that is not toxic whenreleased from the salt upon administration to a recipient.

Acids commonly employed to form pharmaceutically acceptable saltsinclude inorganic acids such as hydrogen bisulfide and hydrochloric,hydrobromic, hydroiodic, sulfuric and phosphoric acids, as well asorganic acids such as para-toluenesulfonic, salicylic, tartaric,bitartaric, ascorbic, maleic, besylic, fumaric, gluconic, glucuronic,formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic,lactic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric,benzoic and acetic acids, and related inorganic and organic acids.Pharmaceutically acceptable salts thus include sulfate, pyrosulfate,bisulfate, sulfite, bisulfate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephthalate, sulfonate, xylenesulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate,.beta.-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate,propanesulfonate, naphthalene-l-sulfonate, naphthalene-2-sulfonate,mandelate and the like salts. Preferred pharmaceutically acceptable acidaddition salts include those formed with mineral acids such ashydrochloric acid and hydrobromic acid, and especially those formed withorganic acids such as maleic acid.

As used herein, the term “hydrate” means a compound which furtherincludes a stoichiometric or non-stoichiometric amount of water bound bynon-covalent intermolecular forces.

As used herein, the term “solvate” means a compound which furtherincludes a stoichiometric or non-stoichiometric amount of a solvent suchas water, acetone, ethanol, methanol, dichloromethane, 2-propanol, orthe like, bound by non-covalent intermolecular forces.

Isotopes and Isotopic Abundance

It will be recognized that some variation of natural isotopic abundanceoccurs in a synthesized compound depending upon the origin of chemicalmaterials used in the synthesis. Thus, a preparation of treprostinilwill inherently contain small amounts of deuterated isotopologues. Theconcentration of naturally abundant stable hydrogen and carbon isotopes,notwithstanding this variation, is small and immaterial with respect tothe degree of stable isotopic substitution of compounds of thisinvention. See, for instance, Wada E et al, Seikagaku 1994, 66:15; GanesL Z et al, Comp Biochem Physiol Mol Integr Physiol 1998, 119:725. In acompound of this invention, when a particular position is designated ashaving deuterium, it is understood that the abundance of deuterium atthat position is substantially greater than the natural abundance ofdeuterium, which is about 0.015%. A position designated as havingdeuterium typically has a minimum isotopic enrichment factor of at leastabout 3000 (about 45% deuterium incorporation) at each atom designatedas deuterium in said compound.

The term “isotopic enrichment factor” as used herein means the ratiobetween the isotopic abundance and the natural abundance of a specifiedisotope.

In some embodiments, a compound of this invention has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

In the compounds of this invention any atom not specifically designatedas a particular isotope is meant to represent any stable isotope of thatatom. Unless otherwise stated, when a position is designatedspecifically as “H” or “hydrogen”, the position is understood to havehydrogen at its natural abundance isotopic composition.

In other embodiment, a compound of the invention contains less than 10%,preferably less than 6%, and more preferably less than 3% of all otherisotopologues combined, including a form that lacks any deuterium. Incertain aspects, the compound contains less than “X”% of all otherisotopologues combined, including a form that lacks any deuterium; whereX is any number between 0 and 10 (e.g., 1, 0.5, 0.001), inclusive.Compositions of matter that contain greater than 10% of all otherisotopologues combined are referred to herein as “mixtures” and mustmeet the parameters set forth below. These limits of isotopiccomposition and all references to isotopic composition herein, refersolely to the relative amounts of deuterium/hydrogen present in theactive, free base form of the compound of Formula I or II, and do notinclude the isotopic composition of hydrolysable portions of prodrugs,or of counterions.

The term “isotopologue” refers to species that differ from a specificcompound of this invention only in the isotopic composition of theirmolecules or ions.

Stereoisomers

It is understood that the present invention encompasses all possiblestereoisomers, including all possible diastereomers and enantiomers, ofthe compounds described herein, and not only the specific stereoisomersas indicated by drawn structure or nomenclature. Some embodiments of theinvention relate to the specific stereoisomers indicated by drawnstructure or nomenclature.

Core Structure Formula I

In one embodiment, the invention provides a compound represented byFormula I:

At least two sub-embodiments are provided to define further Formula I.

In a first sub-embodiment of Formula I, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅,R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ areindependently H or deuterium;

-   Z is —OH, —OR₁₁, —N(R₁₁)R₁₂, —SR₁₁, or P₁;-   R₁₁ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,    haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl,    substituted cycloheteroalkyl, alkylcycloalkyl, substituted    alkylcycloalkyl, alkylcycloheteroalkyl, substituted    alkylcycloheteroalkyl, aryl, substituted aryl, alkylaryl,    substituted alkylaryl, heteroaryl, substituted heteroaryl,    alkylheteroaryl, or substituted alkylheteroaryl;-   R₁₂ is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,    alkylcycloheteroalkyl, aryl, or heteroaryl;-   P₁ is selected from the group consisting of:

wherein,

-   m is 1, 2, 3, or 4;-   R₁₄ and R₁₅ are independently in each occurrence selected from the    group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl,    haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl,    arylalkyl, heteroarylalkyl, substituted aryl, substituted    heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl;-   R₁₄ and R₁₅ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring optionally incorporating one    or two ring heteroatoms chosen from N, O, or S, which is    unsubstituted or substituted with 1, 2, or 3 substituents    independently selected from the group consisting of halo, methyl,    and methoxy;-   R₁₈ and R₁₉ are independently in each occurrence selected from the    group consisting of hydrogen and alkyl, wherein the alkyl is    unsubstituted or substituted with 1 substituent selected from the    group consisting of halo, hydroxy, alkoxy, amino, thio, methylthio,    —C(O)OH, —C(O)O-(alkyl), —CONH₂, aryl, and heteroaryl, wherein the    aryl or heteroaryl are unsubstituted or substituted from the group    consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, and    haloalkoxy;-   R₁₄ and R₁₈ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₄ and R₁₉ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₅ and R₁₈ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₅ and R₁₉ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   and, R₁ and R₂ are independently H or P₂, wherein at least one of R₁    and R₂ is P₂, wherein-   P₂ is selected from the group consisting of:

wherein,

-   m is 1, 2, 3, or 4;-   R₁₄ and R₁₅ are as defined above;-   R₁₄ and R₁₅ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring optionally incorporating one    or two ring heteroatoms chosen from N, O, or S, which is    unsubstituted or substituted with 1, 2, or 3 substituents    independently selected from the list consisting of halo, methyl and    methoxy;-   R₁₆ and R₁₇ are independently in each occurrence H or alkyl;-   R₁₆ and R₁₇ taken together with the atoms to which they attach    optionally form a 3- to 6-membered ring;-   R₁₈ and R₁₉ are as defined above;-   R₁₄ and R₁₈ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₄ and R₁₉ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   wherein Formula I includes enantiomers, pharmaceutically acceptable    salts, solvates and polymorphs of the compounds of Formula I. In    this Formula I, the Z, R₁, and R₂ groups are not linked to each    other, in contrast to Formulae II, III, and IV described herein.

In one embodiment, R₁ is P₂ and R₂ is H. In another embodiment, R₁ is Hand R₂ is P₂. In another embodiment, R₁ is P₂ and R₂ is P₂.

The group P₂ can be more particularly described. In one embodiment, P₂is selected from the group consisting of:

In another embodiment, P₂ is selected from the group consisting of:

In another embodiment, P₂ is selected from the group consisting of:

In another embodiment, P₂ is selected from the group consisting of:

In another embodiment, P₂ is selected from the group consisting of:

In another embodiment, P₂ is selected from the group consisting of:

In another embodiment, P₂ is selected from the group consisting of:

In another embodiment, P₂ is selected from the group consisting of:

In another embodiment, P₂ is selected from the group consisting of:

In another embodiment, P₂ is selected from the group consisting of:

In another embodiment, P₂ is selected from the group consisting of:

In one embodiment, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉,R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are H.

In one embodiment, Z is —OR₁₁, —N(R₁₁)R₁₂, or P₁. In another embodiment,Z is P₁. In another embodiment, Z is —OH, —OR₁₁, —N(R₁₁)R₁₂, or P₁. Inanother embodiment, Z is —OH.

In one embodiment, Z is not —OH and R₁₁ is not unsubstituted orsubstituted benzyl.

In a second sub-embodiment of Formula I,

-   R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂,    R₃₃, R₃₄, R₃₅, and R₃₆ are independently H or deuterium;-   Z is —OR₁₁, —N(R₁₁)R₁₂, —SR₁₁; or P₁;-   R₁₁ is branched alkyl, haloalkyl, halocycloalkyl, heteroalkyl,    substituted heteroalkyl, cycloheteroalkyl, substituted    cycloheteroalkyl, bicycloalkyl, alkylcycloalkyl, substituted    alkylcycloalkyl, alkylcycloheteroalkyl, substituted    alkylcycloheteroalkyl, alkylaryl, substituted alkylaryl, heteroaryl,    substituted heteroaryl, alkylheteroaryl, or substituted    alkylheteroaryl;-   R₁₂ is H, branched alkyl, haloalkyl, heteroalkyl, cycloheteroalkyl,    alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl;-   P₁ is selected from the group consisting of:

wherein,

-   m is 1, 2, 3, or 4;-   R₁₄ and R₁₅ are independently in each occurrence selected from the    group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl,    haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl,    arylalkyl, heteroarylalkyl, substituted aryl, substituted    heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl;-   R₁₄ and R₁₅ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring optionally incorporating one    or two ring heteroatoms chosen from N, O, or S, which is    unsubstituted or substituted with 1, 2, or 3 substituents    independently selected from the group consisting of halo, methyl,    and methoxy;-   R₁₈ and R₁₉ are independently in each occurrence selected from the    group consisting of hydrogen and alkyl, wherein the alkyl is    unsubstituted or substituted with 1 substituent selected from the    list consisting of halo, hydroxy, alkoxy, amino, thio, methylthio,    —C(O)OH, —C(O)O-(alkyl), —CONH₂, aryl, and heteroaryl, wherein the    aryl or heteroaryl is unsubstituted or substituted from the group    consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, and    haloalkoxy;-   R₁₄ and R₁₈ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₄ and R₁₉ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₅ and R₁₈ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₅ and R₁₉ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   and, R₁ and R₂ are independently H or P₂, wherein-   P₂ is selected from the group consisting of:

wherein,

-   m is 1, 2, 3, or 4;-   R₁₄ and R₁₅ are as defined above;-   R₁₄ and R₁₅ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring optionally incorporating one    or two ring heteroatoms chosen from N, O, or S, which is    unsubstituted or substituted with 1, 2, or 3 substituents    independently selected from the list consisting of halo, methyl and    methoxy;-   R₁₆ and R₁₇ are independently in each occurrence H or alkyl;-   R₁₆ and R₁₇ taken together with the atoms to which they attach    optionally form a 3- to 6-membered ring;-   R₁₈ and R₁₉ are as defined above;-   R₁₄ and R₁₈ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₄ and R₁₉ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   wherein Formula I includes enantiomers, pharmaceutically acceptable    salts, solvates and polymorphs of the compounds of Formula I.

In one embodiment, Z is —OR₁₁, In one embodiment, Z is —N(R₁₁)R₁₂. Inone embodiment, Z is —SR₁₁. In one embodiment, Z is P₁. In oneembodiment, Z is OR₁₁ and R₁₁ is bicycloalkyl, alkylcycloalkyl, oralkylcycloheteroalkyl. In one embodiment, Z is P₁.

In one embodiment, R₁₁ is haloalkyl, or more particularly, fluoroalkyl.

In one embodiment, R₁ is hydrogen or R₂ is hydrogen. In one embodiment,R₁ is hydrogen and R₂ is P₂. In one embodiment, R₁ is P₂ and R₂ ishydrogen. In one embodiment, R₁ and R₂ are hydrogen. In one embodiment,R₁ and R₂ are P₂.

In one embodiment, at least one of R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R²⁵, R₂₆,R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ is deuterium.

In one embodiment, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉,R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are hydrogen.

Formula IA

A sub-embodiment of formula I is a compound represented by Formula (IA):

wherein,

-   Z is —OH, —OR₁₁, or P₁;-   R₁₁ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,    haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl,    substituted cycloheteroalkyl, alkylcycloalkyl, substituted    alkylcycloalkyl, alkylcycloheteroalkyl, or substituted    alkylcycloheteroalkyl;-   P₁ is selected from the group consisting of:

wherein,

-   m is 1, 2, 3, or 4;-   R₁₄ is selected from the group consisting of H, alkyl, cycloalkyl,    alkylcycloalkyl, haloalkyl, aryl, heteroaryl, arylalkyl,    heteroarylalkyl, substituted aryl, substituted heteroaryl,    substituted arylalkyl, and substituted heteroarylalkyl;-   and, R₁ and R₂ are independently H or P₂, wherein at least one of R₁    and R₂ is P₂, wherein-   P₂ is selected from the group consisting of:

wherein,

-   R₁₄ and R₁₅ are independently in each occurrence selected from the    group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl,    haloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted    aryl, substituted heteroaryl, substituted arylalkyl, and substituted    heteroarylalkyl;-   R₁₄ and R₁₅ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;

wherein Formula IA includes enantiomers, pharmaceutically acceptablesalts, solvates and polymorphs of the compounds of Formula IA.

Examples of Compounds of Formula I

The following are specific compounds of Formula I (noting Compound A istreprostinil):

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]aceticacid cyclopropylmethyl ester (all possible stereoisomers, includingCompound 1)

N-Cyclopropylmethyl-2-[2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetamide(all possible stereoisomers, including Compound 2)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 2-morpholin-4-yl-ethyl ester (all possible stereoisomers, includingCompound 3)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 3-fluoro-propyl ester (all possible stereoisomers, includingCompound 4)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid tetrahydro-furan-3-yl ester (all possible stereoisomers, includingCompound 5)

2-{2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetoxy}-propionicacid methyl ester (all possible stereoisomers, including Compound 6)

N-(2-Hydroxy-ethyl)-2-[2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetamide(all possible stereoisomers, including Compound 7)

N-(2-Amino-ethyl)-2-[2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetamide(all possible stereoisomers, including Compound 8)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 2-hydroxy-ethyl ester (all possible stereoisomers, includingCompound 9)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 2-methoxy-ethyl ester (all possible stereoisomers, includingCompound 10)

2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-N-(3-hydroxy-propyl)-acetamide(all possible stereoisomers, including Compound 11)

{2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]acetylamino}-aceticacid methyl ester (all possible stereoisomers, including Compound 12)

({2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetyl}-methyl-amino)-aceticacid methyl ester (all possible stereoisomers, including Compound 13)

2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-N-(2,2,2-trifluoro-ethyl)-acetamide(all possible stereoisomers, including Compound 14)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid methyl ester (all possible stereoisomers, including Compound 15)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 2,2-dimethyl-propyl ester (all possible stereoisomers, includingCompound 16)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 1,2-dimethyl-propyl ester (all possible stereoisomers, includingCompound 17)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 1,2,2-trimethyl-propyl ester (all possible stereoisomers, includingCompound 18)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid bicyclo[2.2.1]hept-2-yl ester (all possible stereoisomers,including Compound 19)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid isopropyl ester (all possible stereoisomers, including Compound 20)

2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-N-(2,2,3,3,3-pentafluoro-propyl)-acetamide(all possible stereoisomers, including Compound 21)

Pentanoic acid1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ylester (all possible stereoisomers, including Compound 22)

3-Methyl-butyric acid1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ylester (all possible stereoisomers, including Compound 23)

Cyclopropanecarboxylic acid1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ylester (all possible stereoisomers, including Compound 24)

[2-Ethoxycarbonyloxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid methyl ester (all possible stereoisomers, including Compound 25)

[2-Acetoxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid methyl ester (all possible stereoisomers, including Compound 26)

Succinic acid ethyl ester1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ylester (all possible stereoisomers, including Compound 27)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid tert-butyl ester (all possible stereoisomers, including Compound28)

3-{2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetyl}-oxazolidin-2-one(all possible stereoisomers, including Compound 29)

2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-N-(1H-tetrazol-5-yl)-acetamide(all possible stereoisomers, including Compound 30)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 2,2,2-trifluoro-1,1-dimethyl-ethyl ester (all possiblestereoisomers, including Compound 31)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 1,2,2-trimethyl-propyl ester (all possible stereoisomers, includingCompound 32)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 1,2,2-trimethyl-propyl ester (all possible stereoisomers, includingCompound 33)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid bicyclo[2.2.1]hept-2-yl ester (all possible stereoisomers,including Compound 34)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid bicyclo[2.2.1]hept-2-yl ester (all possible stereoisomers,including Compound 35)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid bicyclo[2.2.1]kept-2-yl ester (all possible stereoisomers,including Compound 36)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid bicyclo[2.2.1]hept-2-yl ester (all possible stereoisomers,including Compound 37)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 2-isopropyl-5-methyl-cyclohexyl ester (all possible stereoisomers,including Compound 38)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl ester (all possiblestereoisomers, including Compound 39)

[2-(2-Ethoxy-ethoxycarbonyloxy)-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid methyl ester (all possible stereoisomers, including Compound 40)

[2-(2-Dimethylamino-ethoxycarbonyloxy)-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid methyl ester (all possible stereoisomers, including Compound 41)

[1-(3-Hydroxy-octyl)-2-(2,2,2-trifluoro-ethoxycarbonyloxy)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid methyl ester (all possible stereoisomers, including Compound 42)

3-Morpholin-4-yl-propionic acid1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ylester (all possible stereoisomers, including Compound 43)

[1-(3-Hydroxy-octyl)-2-(2-pyrrolidin-1-yl-acetoxy)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid methyl ester (all possible stereoisomers, including Compound 44)

Cyclopentanecarboxylic acid1-[2-(2-hydroxy-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-ethyl]-hexylester (all possible stereoisomers, including Compound 45)

1-Methyl-piperidine-2-carboxylic acid1-[2-(2-hydroxy-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-ethyl]-hexylester (all possible stereoisomers, including Compound 46)

4-Methyl-morpholine-2-carboxylic acid1-[2-(2-hydroxy-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-ethyl]-hexylester (all possible stereoisomers, including Compound 47)

Cyclopropanecarboxylic acid1-[2-(2-hydroxy-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-ethyl]-hexylester (all possible stereoisomers, including Compound 48)

2-Methyl-butyric acid1-[2-(2-hydroxy-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-ethyl]-hexylester (all possible stereoisomers, including Compound 49)

[1-(3-Cyclopentyloxycarbonyloxy-octyl)-2-hydroxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid methyl ester (all possible stereoisomers, including Compound 50)

{1-[3-(1-Aza-bicyclo[2.2.2]oct-3-yloxycarbonyloxy)-octyl]-2-hydroxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy}-aceticacid methyl ester (all possible stereoisomers, including Compound 51)

[2-Acetoxy-1-(3-acetoxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 1-aza-bicyclo[2.2.2]oct-3-yl ester (all possible stereoisomers,including Compound 52)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 1-aza-bicyclo[2.2.2]oct-3-yl ester (all possible stereoisomers,including Compound 53)

Propionic acid1-{2-[5-methoxycarbonylmethoxy-2-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyloxy)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl]ethyl}-hexylester (all possible stereoisomers, including Compound 54)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 1,2-dimethyl-propyl ester (all possible stereoisomers, includingCompound 55)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 1,2-dimethyl-propyl ester (all possible stereoisomers, includingCompound 56)

Core Structure Formulae II and IIA

In another embodiment, the invention provides a compound represented byFormula II:

wherein,

-   R₂ is selected from the group consisting of H and P₂;-   R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂,    R₃₃, R₃₄, R₃₅, and R₃₆ are independently selected from the group    consisting of H and deuterium;-   L₁ is selected from the group consisting of —O-alkylene-C(O)—,    —O-alkylene-OC(O)—, or a bond;-   wherein

P₂ is selected from the group consisting of:

wherein,

-   m is 1, 2, 3, or 4;-   R₁₄ and R₁₅ are as defined above;-   R₁₄ and R₁₅ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring optionally incorporating one    or two ring heteroatoms chosen from N, O and S, which is    unsubstituted or substituted with 1, 2, or 3 substituents    independently selected from the group consisting of halo, methyl and    methoxy;-   R₁₆ and R₁₇ are independently in each occurrence H or alkyl;-   R₁₆ and R₁₇ taken together with the atoms to which they attach    optionally form a 3- to 6-membered ring;-   R₁₈ and R₁₉ are as defined above;-   R₁₄ and R₁₈ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₄ and R₁₉ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   wherein Formula II includes enantiomers, pharmaceutically acceptable    salts, solvates and polymorphs of the compounds of Formula II.

In one embodiment, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉,R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are H. In one embodiment, at leastone of R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂,R₃₃, R₃₄, R₃₅, and R₃₆ is deuterium.

In one embodiment, L₁ is selected from the group consisting of—O-alkyl-C(O)— and —O-alkyl-OC(O)—. In one embodiment, L₁ is—O-alkylene-C(O)—. In one embodiment, L₁ is —O-alkylene-OC(O)—. In oneembodiment, the alkylene group of claim 41 is a C₁-C₅ alkylene group. Inone embodiment, the alkylene group of claim 41 is a C₁ alkylene group.

In one sub-embodiment of Formula II, provided is a compound according toclaim 41, wherein the compound is represented by Formula IIA:

wherein L₁ and R₂ are defined as in Formula II.

Examples of Compounds of Formula II

The following represent specific compounds of Formula II:

Treprostinil 2-hydroxy lactone (all possible stereoisomers, includingCompound 57)

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid carboxymethyl lactone (all possible stereoisomers, includingCompound 58)

Core Structure Formula III

In one embodiment, the invention provides a compound represented byFormula III:

wherein L₂ is selected from the group consisting of —CH₂—, —CHMe-,—C(Me)₂- and the following:

wherein,

-   m is 1, 2, 3, or 4;-   X is NR₁₄ or O;-   R₁₄ is selected from the group consisting of H, alkyl, cycloalkyl,    alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl,    heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl,    substituted heteroaryl, substituted arylalkyl, and substituted    heteroarylalkyl;-   R₁₆ and R₁₇ are independently in each occurrence H or alkyl;-   R₁₆ and R₁₇ taken together with the atoms to which they attach    optionally form a 3- to 6-membered ring; and-   R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂,    R₃₃, R₃₄, R₃₅, and R₃₆ are independently selected from the group    consisting of H and deuterium;-   wherein Z is —OH, —OR₁₁, —N(R₁₁)R₁₂, —SR₁₁, or P₁;-   R₁₁ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,    haloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl,    substituted cycloheteroalkyl, alkylcycloalkyl, substituted    alkylcycloalkyl, alkylcycloheteroalkyl, substituted    alkylcycloheteroalkyl, aryl, substituted aryl, alkylaryl,    substituted alkylaryl, heteroaryl, substituted heteroaryl,    alkylheteroaryl, or substituted alkyl heteroaryl;-   R₁₂ is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,    alkylcycloheteroalkyl, aryl, or heteroaryl;-   P₁ is selected from the group consisting of:

wherein,

-   m is 1, 2, 3, or 4;-   R₁₄ and R₁₅ are independently in each occurrence selected from the    group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl,    haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl,    arylalkyl, heteroarylalkyl, substituted aryl, substituted    heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl;-   R₁₄ and R₁₅ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring optionally incorporating one    or two ring heteroatoms chosen from N, O and S, which is    unsubstituted or substituted with 1, 2, or 3 substituents    independently selected from the group consisting of halo, methyl,    and methoxy;-   R₁₈ and R₁₉ are independently in each occurrence selected from the    group consisting of hydrogen and alkyl, wherein the alkyl is    unsubstituted or substituted with I substituent selected from the    list consisting of halo, hydroxy, alkoxy, amino, thio, methylthio,    —C(O)OH, —C(O)O-(alkyl), —CONH₂, aryl, and heteroaryl, wherein the    aryl or heteroaryl is unsubstituted or substituted from the list    consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, and    haloalkoxy;-   R₁₄ and R₁₈ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₄ and R₁₉ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₅ and R₁₈ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₅ and R₁₉ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   wherein Formula III includes enantiomers, pharmaceutically    acceptable salts, solvates and polymorphs of the compounds of    Formula III.

In one embodiment, L₂ is selected from the group consisting of:

In one embodiment, at least one of R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆,R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ is deuterium, orthey are all hydrogen.

One particular sub-embodiment of Formula III includes a compoundrepresented by Formula IIIA:

wherein Z and L₂ are defined as in Formula III.

Examples of Compounds of Formula III

The following compounds represent specific examples of Formula IIIcompounds:

[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid methyl ester 2,3-maleate (all possible stereoisomers, includingCompound 59)

Core Structure Formula IV

Another embodiment is a compound represented by Formula IV, whereinunlike in Formula II, the L₁ group links to R₂ rather than R₁:

wherein R₁ is selected from the group consisting of H and P₂;

-   R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂,    R₃₃, R₃₄, R₃₅, and R₃₆ are independently selected from the group    consisting of H and deuterium;-   L₁ is a selected from the group consisting of —O-alkylene-C(O)—,    —O-alkylene-OC(O)—, and a bond; wherein-   P₂ is selected from the group consisting of:

wherein,

-   m is 1, 2, 3, or 4;-   R₁₄ and R₁₅ are independently in each occurrence selected from the    group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl,    haloalkyl, heteroalkyl, substituted alkyl, aryl, heteroaryl,    arylalkyl, heteroarylalkyl, substituted aryl, substituted    heteroaryl, substituted arylalkyl, and substituted heteroarylalkyl;-   R₁₄ and R₁₅ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring optionally incorporating one    or two ring heteroatoms chosen from N, O and S, which is    unsubstituted or substituted with 1, 2, or 3 substituents    independently selected from the group consisting of halo, methyl,    and methoxy;-   R₁₆ and R₁₇ are independently in each occurrence H or alkyl;-   R₁₆ and R₁₇ taken together with the atoms to which they attach    optionally form a 3- to 6-membered ring;-   R₁₈ and R₁₉ are independently in each occurrence selected from the    group consisting of hydrogen and alkyl, wherein the alkyl is    unsubstituted or substituted with 1 substituent selected from the    list consisting of halo, hydroxy, alkoxy, amino, thio, methylthio,    —C(O)OH, —C(O)O-(alkyl), —CONH₂, aryl, and heteroaryl, wherein the    aryl or heteroaryl is unsubstituted or substituted from the list    consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, and    haloalkoxy;-   R₁₄ and R₁₈ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   R₁₄ and R₁₉ taken together with the atoms to which they attach    optionally form a 5- to 7-membered ring;-   wherein Formula IV includes enantiomers, pharmaceutically acceptable    salts, solvates and polymorphs of the compounds of Formula IV.

In one embodiment, at least one of R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆,R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ is deuterium, orthey are all hydrogen.

In a particular embodiment of Formula IV, a compound is represented byFormula IVA:

wherein L₁ and R₁ are defined as in Formula IV.

Similar approaches can be used to make and use Formula IV compounds asfor Formula II compounds.

Embodiments from Priority Provisional 61/751,608

One embodiment from the priority provisional is a compound according toFormula (IAA).

wherein,

-   R₁₀₀ and R₂₀₀ are independently selected from the group consisting    of H, —CONR₉₀₀R₁₀₀₀, —CR₉₀₀R₁₀₀₀OCOP₃R₉₀₀(R₁₀₀₀), wherein R₉₀₀ and    R₁₀₀₀ are independently selected from H, alkyl, and cycloalkyl;-   R₃₀₀, R₄₀₀, R₅₀₀, R₆₀₀, R₇₀₀ and R₈₀₀ are independently selected    from the group consisting of H and deuterium;-   X is O, —NHR₁₂₀₀, or S;-   P₃ is N or O;-   R₁₁₀₀ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,    alkylcycloheteroalkyl, aryl, or heteroaryl;-   R₁₂₀₀ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,    alkylcycloheteroalkyl, aryl, heteroaryl.

In one embodiment, R₁₀₀ and R₂₀₀ are H. In one embodiment, R₃₀₀, R₄₀₀,R₅₀₀, R₆₀₀, R₇₀₀ and R₈₀₀ are H. In one embodiment, X is O. In oneembodiment, R₁₁₀₀ is selected from the group consisting of:

In one embodiment, X is —NHR₁₂₀₀.

In one embodiment, R₁₁₀₀ is chosen from the group consisting of:

In one embodiment, X is O. In one embodiment, R₃₀₀, R₄₀₀, R₅₀₀, R₆₀₀,R₇₀₀ and R₈₀₀ are H. In one embodiment, R₁₁₀₀ is alkyl.

Another embodiment from the priority provisional is a compound ofFormula II(AA):

wherein,

-   R₂₀₀₀ is independently selected from the group consisting of H,    —CONR₉₀₀₀R₁₀₀₀₀. —CR₉₀₀₀R₁₀₀₀₀OCOP₄R₉₀₀₀(R₁₀₀₀₀), wherein R₉₀₀₀ and    R₁₀₀₀₀ are independently selected from H, alkyl, and cycloalkyl;-   R₃₀₀₀, R₄₀₀₀, R₅₀₀₀, R₆₀₀₀, R₇₀₀₀ and R₈₀₀₀ are independently    selected from the group consisting of H and deuterium;-   X is O, —NR₁₂₀₀₀ or S;-   P₄ is N or O;-   R₁₂₀₀₀ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,    alkylcycloheteroalkyl, aryl, or heteroaryl;-   n is an integer between 1 and 7;-   wherein compounds of Formula II(AA) include enantiomers,    pharmaceutically acceptable salts, solvates and polymorphs of the    compounds of Formula II(AA).

Another embodiment from the priority provisional is a compound havingFormula III(AA):

wherein,

-   R₁₁ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,    alkylcycloheteroalkyl, aryl, or heteroaryl;-   R₀₃, R₀₄, R₀₅, R₀₆, R₀₇ and R₀₈ are independently selected from the    group consisting of H and deuterium;-   X is O, —NR₀₁₂ or S;-   R₀₁₂ is haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,    alkylcycloheteroalkyl, aryl, or heteroaryl;-   Y is C═O, —CH₂—, —CHMe-, or —C(Me)₂-;-   and compounds of Formula III(AA) include enantiomers,    pharmaceutically acceptable salts, solvates and polymorphs of the    compounds of Formula III(AA).

Methods of Making Compounds of Formula I

The compounds of formula I where R₁ and R₂ are H can be synthesizedaccording to Scheme 1 by starting with the compound of Formula I where Zis OH and R₁ is H and R₂ is PG which represents a protective group asdescribed in Protective Groups in Organic Synthesis by Greene and Wuts.The carboxylic acid is activated using coupling conditions which involvethe use of an activating agent, including but not limited to EDC, DCC,DIC, BOP, HATU, HBTU, CDI, thionyl chloride, or oxalyl chloride.Coupling conditions may also include or not include an additive,including but not limited to DMF, HOSu, HOBT, or HOAT, and may or maynot include one or more nucleophilic or non-nucleophilic bases oradditives including, but not limited to, DMAP, TEA, DIPEA,N-methylmorpholine, pyridine, and/or imidazole. Coupling conditions alsomay be run in a suitable solvent or solvent mixture including, but notlimited to, DCM, THF, DMF, dioxane, ethyl acetate, and/or acetonitrile.The activated acid can be isolated and purified or can be treateddirectly with the reagent ZH. Alternately, ZH can be present during thecoupling conditions. Representative examples of coupling conditions anddefinitions of the activating agents, additives and bases can be foundin in Handbook of Reagents for Organic Synthesis: Activating Agents andProtecting Groups, John Wiley and Sons. The resulting compound ofFormula I where Z is not OH, R₁ is H and R₂ is PG is deprotected usingdeprotection conditions suitable to the type of protective grouprepresented by PG to give the compound of Formula I. Examples ofsuitable deprotection conditions can be found in Protective Groups inOrganic Synthesis by Greene and Wuts.

The compound of Formula I where R₁═R₂ or where R₁ is H can besynthesized according to Scheme 2 starting from the compound of FormulaI where R₁ and R₂ are H by employing acylation conditions and thereactive molecule ROH or RY, where Y is a leaving group including, butnot limited to, halogen, sulfonyl, phosphoryl, or acyl. In the casewhere the reactive molecule ROH is used, acylation conditions aresimilar to coupling conditions as described above. In the case where thereactive molecule RY is used, the acylation conditions may or may notinclude one or more nucleophilic or non-nucleophilic bases or additivesincluding but not limited to DMAP, TEA, DIPEA, N-methylmorpholine,pyridine, and/or imidazole and may be run in a suitable solvent orsolvent mixture including, but not limited to DCM, THF, DMF, dioxane,ethyl acetate, and/or acetonitrile.

The compounds of Formula I where R₂ is H can be synthesized according toScheme 3 starting from the compound of Formula I where R₁ is H and R₂ isPG as described above, by employing acylation conditions using ROH or RYas described above followed by deprotection conditions as describedabove.

Methods of Making Compounds of Formula II

The compounds of Formula II can be synthesized according to Scheme 4starting from the compound of Formula I where Z is OH and R₂ is PG asdescribed above, by employing lactonization conditions. Examples oflactonization conditions can be found in Chemical Reviews (2007), 107,239 and Beilstein Journal of Organic Chemistry (2012), 8, 1344, andinclude but are not limited to 2,4,6-trichlorobenzoic anhydride, TEA andDMAP; 4-nitrobenzoic anhydride, TEA, and DMAP;2-chloro-1-methylpyridinium iodide and tributyl amine; 2,2′-dipyridyldisulfide and triphenylphosphine; and all the reactions in the couplingconditions and acylation conditions described above. The lactonizationreactions may be run in a suitable solvent or solvent mixture including,but not limited to DCM, THF, DMF, dioxane, ethyl acetate, acetonitrileand/or toluene.

Methods of Making Compounds of Formula III

The compounds of Formula III can be synthesized according to Scheme 5starting with the compound of Formula I where R₁ and R₂ are H, byreacting with an activated carbonyl equivalent including but not limitedto phosgene, carbonyl diimidazole, or 4-nitrophenyl chloroformate, inthe presence or absence of one or more nucleophilic or non-nucleophilicbases or additives including but not limited to DMAP, TEA, DIPEA,N-methylmorpholine, pyridine, and/or imidazole and may be run in asuitable solvent or solvent mixture including but not limited to DCM,THF, DMF, dioxane, ethyl acetate, acetonitrile, and/or toluene.

Pharmaceutical Compositions

The compounds described herein can be used alone or in combination withother components as known in the art. In particular, formulations ofmultiple ingredients can be prepared that are adapted for use inprophylactic and therapeutic treatments. The composition can be in theform of, for example, a solid, liquid, semi-solid, solution, suspension,or emulsion formulation. Water can be used as a formulation agent. Itcan be in pure form or combined with one or more excipients.

In one embodiment, the compound is formulated in matrix form, comprisinga matrix material in which drug is contained or dispersed. The matrixmaterial further controls release of the drug by controlling dissolutionand/or diffusion of the drug from the reservoir, and may enhancestability of the drug molecule while stored in the reservoir. In oneembodiment, the drug is formulated with an excipient material that isuseful for accelerating release, e.g., a water-swellable material thatcan aid in pushing the drug out of the reservoir and through any tissuecapsule over the reservoir. Examples include hydrogels and osmoticpressure generating agents known in the art. In another embodiment, thedrug is formulated with a penetration enhancer(s). The penetrationenhancer further controls release of the drug by facilitating transportof the drug across the skin into the local administration site orsystemic delivery.

More particularly, the drug can be dispersed in a matrix material, tofurther control the rate of release of drug. This matrix material can bea “release system,” as described in U.S. Pat. No. 5,797,898, thedegradation, dissolution, or diffusion properties of which can provide amethod for controlling the release rate of the chemical molecules.

The release system may provide a temporally modulated release profile(e.g., pulsatile release) when time variation in plasma levels isdesired or a more continuous or consistent release profile when aconstant plasma level as needed to enhance a therapeutic effect, forexample. Pulsatile release can be achieved from an individual reservoir,from a plurality of reservoirs, or a combination thereof. For example,where each reservoir provides only a single pulse, multiple pulses(i.e., pulsatile release) are achieved by temporally staggering thesingle pulse release from each of several reservoirs. Alternatively,multiple pulses can be achieved from a single reservoir by incorporatingseveral layers of a release system and other materials into a singlereservoir. Continuous release can be achieved by incorporating a releasesystem that degrades, dissolves, or allows diffusion of moleculesthrough it over an extended period. In addition, continuous release canbe approximated by releasing several pulses of molecules in rapidsuccession (“digital” release). The active release systems describedherein can be used alone or on combination with passive release systems,for example, as described in U.S. Pat. No. 5,797,898.

The pharmaceutical agent can be formulated with one or morepharmaceutically acceptable excipients. Representative examples includebulking agents, wetting agents, stabilizers, crystal growth inhibitors,antioxidants, antimicrobials, preservatives, buffering agents (e.g.,acids, bases), surfactants, desiccants, dispersants, osmotic agents,binders (e.g., starch, gelatin), disintegrants (e.g., celluloses),glidants (e.g., talc), diluents (e.g., lactose, dicalcium phosphate),color agents, lubricants (e.g., magnesium stearate, hydrogenatedvegetable oils) and combinations thereof. In some embodiments, theexcipient is a wax or a polymer. In one embodiment, the polymercomprises polyethylene glycol (PEG), e.g., typically one having amolecular weight between about 100 and 10,000 Daltons (e.g., PEG 200,PEG 1450). In another embodiment, the polymer comprises poly lactic acid(PLA), poly glycolic acid (PGA), copolymers thereof (PLGA), orethyl-vinyl acetate (EVA) polymers. In yet another embodiment, theexcipient material comprises a pharmaceutically acceptable oil (e.g.,sesame oil).

In one embodiment, the excipient material includes a saturated drugsolution. That is, the excipient material comprises a liquid solutionformed of the drug dissolved in a solvent for the drug. The solution issaturated so that the solvent does not dissolve the solid matrix form ofthe drug. The saturated solution acts as a non-solvent excipientmaterial, substantially filling pores and voids in the solid matrix.

In another embodiment, the excipient material comprises apharmaceutically acceptable perhalohydrocarbon or unsubstitutedsaturated hydrocarbon. See, for example, U.S. Pat. No. 6,264,990 toKnepp et al, which describes anhydrous, aprotic, hydrophobic, non-polarliquids, such as biocompatible perhalohydrocarbons or unsubstitutedsaturated hydrocarbons, such as perfluorodecalin, perflurobutylamine,perfluorotripropylamine, perfluoro-N-methyldecahydroquindine,perfluoro-octohydro quinolidine, perfluoro-N-cyclohexylpyrilidine,perfluoro-N,N-dimethylcyclohexyl methylamine,perfluoro-dimethyl-adamantane, perfluorotri-methylbicyclo (3.3.1)nonane, bis(perfluorohexyl) ethene, bis(perfluorobutyl) ethene,perfluoro-1-butyl-2-hexyl ethene, tetradecane, methoxyflurane andmineral oil.

In one embodiment, the pharmaceutically acceptable excipient materialcomprises dimethyl sulfoxide (DMSO), glycerol, or ethanol.

Mixtures of compounds according to Formulae I, II, III, and IV can beused.

As noted above, a pharmaceutical composition can comprise a treprostinilderivative or a pharmaceutically acceptable salt, solvate, clathrate orpolymorph thereof, and one or more pharmaceutically acceptable carriersor excipients. The composition can optionally contain an additionaltherapeutic agent.

Pharmaceutically acceptable carriers and excipients includepharmaceutically acceptable materials, vehicles and substances.Non-limiting examples of excipients include liquid and solid fillers,diluents, binders, lubricants, glidants, surfactants, dispersing agents,disintegration agents, emulsifying agents, wetting agents, suspendingagents, thickeners, solvents, isotonic agents, buffers, pH adjusters,absorption-delaying agents, sweetening agents, flavoring agents,coloring agents, stabilizers, preservatives, antioxidants, antimicrobialagents, antibacterial agents, antifungal agents, adjuvants,encapsulating materials and coating materials. The use of suchexcipients in pharmaceutical formulations is known in the art. Exceptinsofar as any conventional carrier or excipient is incompatible withthe active ingredient, the disclosure encompasses the use ofconventional carriers and excipients in formulations containingtreprostinil derivatives. See, e.g., Remington: The Science and Practiceof Pharmacy, 21st Ed., Lippincott Williams & Wilkins (Philadelphia,Penn. [2005]); Handbook of Pharmaceutical Excipients, 5th Ed., Rowe etal., Eds., The Pharmaceutical Press and the American PharmaceuticalAssociation (2005); Handbook of Pharmaceutical Additives, 3rd Ed., Ashand Ash, Eds., Gower Publishing Co. (2007); and PharmaceuticalPreformulation and Formulation, Gibson, Ed., CRC Press LLC (Boca Raton,Fla. [2004]).

Proper formulation can depend on various factors, such as the route ofadministration chosen. Potential routes of administration ofpharmaceutical compositions comprising treprostinil derivatives includewithout limitation oral, parenteral (including intramuscular,subcutaneous, intradermal, intravascular, intravenous, intraarterial,intramedullary and intrathecal), intraperitoneal, and topical (includingdermal/epicutaneous, transdermal, mucosal, transmucosal, intranasal[e.g., by nasal spray or drop], intraocular [e.g., by eye drop],pulmonary [e.g., by inhalation], buccal, sublingual, rectal andvaginal).

As an example, formulations of treprostinil derivatives suitable fororal administration can be presented as, e.g., capsules (includingpush-fit capsules and soft capsules), cachets or tablets; as powders orgranules; or as boluses, electuaries or pastes. For example, push-fitcapsules can contain a treprostinil derivative in admixture with, e.g.,a filler (e.g., lactose), a binder (e.g., a starch) and a lubricant(e.g., talc or magnesium stearate), and optionally a stabilizer. Forsoft capsules, a treprostinil derivative can be dissolved or suspendedin a suitable liquid (e.g., a fatty oil, liquid paraffin or liquidpolyethylene glycol), and a stabilizer can be added.

Compositions for oral administration can also be formulated as solutionsor suspensions in an aqueous liquid and/or a non-aqueous liquid, or asoil-in-water liquid emulsions or water-in-oil liquid emulsions.Dispersible powder or granules of a treprostinil derivative can be mixedwith any suitable combination of an aqueous liquid, an organic solventand/or an oil and any suitable excipients (e.g., any combination of adispersing agent, a wetting agent, a suspending agent, an emulsifyingagent and/or a preservative) to form a solution, suspension or emulsion.

Treprostinil derivatives can also be formulated for parenteraladministration by injection or infusion. Formulations for injection orinfusion can be in the form of, e.g., solutions, suspensions oremulsions in oily or aqueous vehicles, and can contain excipients suchas suspending agents, dispersing agents and/or stabilizing agents. Forexample, aqueous or non-aqueous (e.g., oily) sterile injection solutionscan contain a treprostinil derivative along with excipients such as anantioxidant, a buffer, a bacteriostat and solutes that render theformulation isotonic with the blood of the subject. Aqueous ornon-aqueous sterile suspensions can contain a treprostinil derivativealong with excipients such as a suspending agent and a thickening agent,and optionally a stabilizer and an agent that increases the solubilityof the treprostinil derivative to allow for the preparation of a moreconcentrated solution or suspension. As another example, a sterileaqueous solution for injection or infusion (e.g., subcutaneously orintravenously) can contain a treprostinil derivative, sodium chloride, abuffering agent (e.g., sodium citrate), a preservative (e.g.,meta-cresol), and optionally a base (e.g., NaOH) and/or an acid (e.g.,HCl) to adjust pH.

For a delayed or sustained release of a treprostinil derivative, acomposition can be formulated as a depot that can be implanted in orinjected into a subject, e.g., intramuscularly or subcutaneously. Adepot formulation can be designed to deliver the treprostinil derivativeover a longer period of time, e.g., over at least about 1 week, 2 weeks,3 weeks, 1 month, 1.5 months, 2 months or longer. For example, atreprostinil derivative can be formulated with a polymeric material, ahydrophobic material (e.g., as an emulsion in an oil) and/or anion-exchange resin, or as a sparingly soluble derivative (e.g., asparingly soluble salt).

In some embodiments, a topical dosage form of a treprostinil derivativeis formulated as a buccal or sublingual tablet or pill. Advantages of abuccal or sublingual tablet or pill include avoidance of first-passmetabolism and circumvention of gastrointestinal absorption. A buccal orsublingual tablet or pill can also be designed to provide faster releaseof the treprostinil derivative for more rapid uptake of it into systemiccirculation. In addition to a therapeutically effective amount of atreprostinil derivative, the buccal or sublingual tablet or pill cancontain suitable excipients, including without limitation anycombination of fillers and diluents (e.g., mannitol and sorbitol),binding agents (e.g., sodium carbonate), wetting agents (e.g., sodiumcarbonate), disintegrants (e.g., crospovidone and croscarmellosesodium), lubricants (e.g., silicon dioxide [including colloidal silicondioxide] and sodium stearyl fumarate), stabilizers (e.g., sodiumbicarbonate), flavoring agents (e.g., spearmint flavor), sweeteningagents (e.g., sucralose), and coloring agents (e.g., yellow iron oxide).

In addition, treprostinil derivatives can be formulated for intranasaladministration. Intranasal administration avoids first-pass metabolismand can introduce a significant concentration of a treprostinilderivative to the central nervous system, which can reduce side-effects.An intranasal formulation can comprise a treprostinil derivative alongwith excipients such as a solubility enhancer (e.g., propylene glycol),a humectant (e.g., mannitol or sorbitol), a buffer and water, andoptionally a preservative (e.g., benzalkonium chloride), a mucoadhesiveagent (e.g., hydroxyethylcellulose) and/or a penetration enhancer.

Furthermore, treprostinil derivatives can be formulated foradministration by oral inhalation. Advantages of administration byinhalation include selective deposition of the therapeutic agent in thelungs with less systemic side effects. In certain embodiments, a sterileaqueous solution for oral inhalation contains a treprostinil derivative,sodium chloride, a buffering agent (e.g., sodium citrate), optionally apreservative (e.g., meta-cresol), and optionally a base (e.g., NaOH)and/or an acid (e.g., HCl) to adjust pH.

The pharmaceutical compositions can be manufactured in any suitablemanner known in the art, e.g., by means of conventional mixing,dissolving, suspending, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or compressing processes.

The compositions can be presented in unit dosage form as a single dosewherein all active and inactive ingredients are combined in a suitablesystem, and components do not need to be mixed to form the compositionto be administered. The unit dosage form can contain an effective dose,or an appropriate fraction thereof, of a treprostinil derivative. Arepresentative example of a unit dosage form is a tablet, capsule, orpill for oral uptake. For purposes of the content of a pharmaceuticalcomposition, the term “active ingredient” encompasses a prodrug.

Alternatively, the compositions can be presented as a kit, wherein theactive ingredient, excipients and carriers (e.g., solvents) are providedin two or more separate containers (e.g., ampules, vials, tubes, bottlesor syringes) and need to be combined to form the composition to beadministered. The kit can contain instructions for preparing andadministering the composition (e.g., a solution to be injectedintravenously).

Topical Compositions

Topical formulations for application to the skin or mucosa can be usefulfor transdermal or transmucosal administration of a therapeutic agentinto the blood for systemic distribution. Advantages of topicaladministration can include avoidance of first-pass metabolism,circumvention of gastrointestinal absorption, delivery of a therapeuticagent with a relatively short biological half-life, more controlledrelease of the therapeutic agent, administration of a more uniformplasma dosing of the therapeutic agent, and improvement in usercompliance.

In general and in addition to the disclosure on topical formulationsdescribed elsewhere herein, compositions suitable for topicaladministration include without limitation liquid or semi-liquidpreparations such as sprays, gels, liniments, lotions, oil-in-water orwater-in-oil emulsions such as creams, foams, ointments and pastes, andsolutions or suspensions such as drops (e.g., eye drops, nose drops andear drops). In some embodiments, a topical composition comprises atherapeutic agent dissolved, dispersed or suspended in a carrier. Thecarrier can be in the form of, e.g., a solution, a suspension, anemulsion, an ointment or a gel base, and can contain, e.g., petrolatum,lanolin, a wax (e.g., bee wax), mineral oil, a long-chain alcohol,polyethylene glycol or polypropylene glycol, a diluent (e.g., waterand/or an alcohol [e.g., ethanol or propylene glycol]), an emulsifier, astabilizer or a thickening agent, or a combination thereof. A topicalcomposition can include, or a topical formulation can be administered bymeans of, e.g., a transdermal patch, a microneedle patch or aniontophoresis device. A transdermal patch can contain, e.g., amicroporous membrane made of a suitable material (e.g., cellulosenitrate or acetate, propylene or a polycarbonate), a skin adhesive andbacking material. A topical composition can deliver the therapeuticagent transdermally (including percutaneously and transmucosally) via aconcentration gradient or an active mechanism (e.g., ionospheres).

Representative kinds of topical compositions are described below forpurposes of illustration.

Topical Compositions Comprising a Permeation Enhancer

In some embodiments, a topical composition comprises a treprostinilderivative and a permeation enhancer. The composition can optionallycontain an additional therapeutic agent.

The permeation enhancer increases the permeability of the skin or mucosato the therapeutic agent(s). In certain embodiments, the permeationenhancer is N-lauroyl sarcosine, sodium octyl sulfate, methyl laurate,isopropyl myristate, oleic acid, glyceryl oleate or sodium laurylsulfoacetate, or a combination thereof. In certain embodiments, thecomposition contains on a weight/volume (w/v) basis the permeationenhancer in an amount of about 1-20%, 1-15%, 1-10% or 1-5%. To enhancefurther the ability of the therapeutic agent(s) to penetrate the skin ormucosa, the composition can also contain a surfactant, an azone-likecompound, an alcohol, a fatty acid or ester, or an aliphatic thiol.

The composition can further contain one or more additional excipients.Suitable excipients include without limitation solubilizers (e.g., C₂-C₈alcohols), moisturizers or humectants (e.g., glycerol [glycerin],propylene glycol, amino acids and derivatives thereof, polyamino acidsand derivatives thereof, and pyrrolidone carboxylic acids and salts andderivatives thereof), surfactants (e.g., sodium laureth sulfate andsorbitan monolaurate), emulsifiers (e.g., cetyl alcohol and stearylalcohol), thickeners (e.g., methyl cellulose, ethyl cellulose,hydroxymethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone,polyvinyl alcohol and acrylic polymers), and formulation bases orcarriers (e.g., polyethylene glycol as an ointment base). As anon-limiting example, the base or carrier of the composition can containethanol, propylene glycol and polyethylene glycol (e.g., PEG 300), andoptionally an aqueous liquid (e.g., isotonic phosphate-buffered saline).

The topical composition can have any suitable dosage form, such as asolution (e.g., eye drop, nose drop or ear drop), a suspension, anemulsion, a cream, a lotion, a gel, an ointment, a paste, a jelly, afoam, or a spray. In some embodiments, the composition is applied to theskin or mucosa covering a surface area of about 10-800 cm², 10-400 cm²or 10-200 cm². The composition can be formulated for transdermal ortransmucosal administration of the therapeutic agent(s) to the systemiccirculation, e.g., as a transdermal patch or a microneedle patch.

Topical Compositions Comprising a Permeation Enhancer and a VolatileLiquid

In further embodiments, a topical composition comprises a treprostinilderivative, a permeation enhancer and a volatile liquid. The compositioncan optionally contain an additional therapeutic agent.

The permeation enhancer increases the permeability of the skin or mucosato the therapeutic agent(s). In some embodiments, the permeationenhancer is selected from the group consisting of C₈-C₁₈ alkylaminobenzoates (e.g., C₈-C₁₈ alkyl p-aminobenzoates), C₈-C₁₈ alkyldimethylaminobenzoates (e.g., C₈-C₁₈ alkyl p-dimethylaminobenzoates),C₈-C₁₈ alkyl cinnamates, C₈-C₁₈ alkyl methoxycinnamates (e.g., C₈-C₁₈alkyl p-methoxycinnamates), and C₈-C₁₈ alkyl salicylates. In certainembodiments, the permeation enhancer is octyl salicylate, octylp-dimethylaminobenzoate or octyl p-methoxycinnamate, or a combinationthereof.

The volatile liquid can be any volatile, skin- or mucosa-tolerantsolvent. In certain embodiments, the volatile liquid is a C₂-C₅ alcoholor an aqueous solution thereof, such as ethanol or isopropanol or anaqueous solution thereof. An aerosol propellant (e.g., dimethyl ether)can be considered as a volatile liquid. In some embodiments, thevolatile liquid functions as a carrier or vehicle of the composition.

The composition can optionally contain a thickening agent. Non-limitingexamples of thickening agents include cellulosic thickening agents(e.g., ethyl cellulose, hydroxypropyl cellulose and hydroxypropylmethylcellulose), povidone, polyacrylic acids/polyacrylates (e.g.,Carbopol® polymers), Sepigel® (polyacrylamide/isoparaffin/laureth-7),and the Gantrez® series of polymethyl vinyl ether/maleic anhydridecopolymers (e.g., butyl ester of PMV/MA copolymer Gantrez® A-425).

In some embodiments, the composition contains on a weight basis about0.1-5%, 0.5-5% or 1-5% of a treprostinil derivative, about 1-20%, 1-15%or 1-10% of the permeation enhancer, and about 40-98%, 45-95%, 50-90% or60-80% of the volatile liquid. In further embodiments, the compositionoptionally contains on a weight basis about 1-40%, 1-30%, 1-20% or 5-20%water and/or about 0.1-15%, 0.5-10% or 1-5% of a thickening agent.

For purposes of illustration, in certain embodiments a topical spraycomposition contains about 0.1-5% w/v of a treprostinil derivative,about 2-10% w/v of octyl salicylate or octyl p-methyoxycinnamate, andabout 95% aqueous ethanol as the carrier. In further embodiments, atopic gel composition comprises about 0.1-5% w/v of a treprostinilderivative, about 1-10% w/v of octyl salicylate or octylp-methyoxycinnamate, about 0.5-5% w/v of a Carbopol® polyacrylic acid,and about 70% aqueous ethanol as the carrier, and optionally about 1-10%w/v of a basic solution (e.g., 0.1 N NaOH). In additional embodiments, atopical lotion composition contains about 0.1-5% w/v of a treprostinilderivative, about 1-10% w/v of octyl salicylate or octylp-methyoxycinnamate, about 1-5% w/v of ethyl cellulose or hydroxypropylcellulose, and about 90% aqueous ethanol as the carrier.

The composition can further comprise other excipients, such as acompounding agent (e.g., paraffin oil, silicone oil, a vegetable oil, ora fatty ester such as isopropyl myristate), a diluent, a co-solvent(e.g., acetone or a glycol ether such as diethylene glycol monoethylether), an emulsifier, a surfactant (e.g., an ethoxylated fatty alcohol,glycerol mono stearate or a phosphate ester), a stabiliser, anantioxidant or a preservative (e.g., a hydroxybenzoate ester), or acombination thereof. For example, a co-solvent and/or a surfactant canbe used to maintain the therapeutic agent(s) in solution or suspensionat the desired concentration.

The topical composition can have any suitable dosage form, such as acream, a lotion, a gel, an ointment, a mousse, a spray or aerosol, orany transdermal device (e.g., a patch) that administers a drug byabsorption through the skin or mucosa. In some embodiments, the topicalcomposition is applied to the skin or mucosa covering a surface area ofabout 10-800 cm², 10-400 cm² or 10-200 cm².

Topical Compositions Including a Permeation Enhancer and AnotherExcipient

In yet further embodiments, a topical composition comprises atreprostinil derivative, a permeation enhancer, and at least one of alipophilic solvent, a formulation base and a thickener. In someembodiments, the composition contains a lipophilic solvent and aformulation base, or the same substance can function as both alipophilic solvent and a formulation base. In further embodiments, thecomposition contains a lipophilic solvent, a formulation base and athickener. The composition can optionally comprise an additionaltherapeutic agent.

The permeation enhancer increases the permeability of the skin or mucosato the therapeutic agent(s). Non-limiting examples of permeationenhancers include dimethyl sulfoxide (DMSO), decylmethylsulfoxide,laurocapram, pyrrolidones (e.g., 2-pyrrolidone andN-methyl-2-pyrrolidine), surfactants, alcohols (e.g., oleyl alcohol),polyethylene glycol (e.g., PEG 400), diethylene glycol monoethyl ether,oleic acid, and fatty acid esters (e.g., isopropyl myristate, methyllaurate, glycerol monooleate, and propylene glycol monooleate).

Non-limiting examples of liphophilic solvents include lipophilicalcohols (e.g., hexylene glycol, octyldodecanol, oleyl alcohol andstearyl alcohol), polyethylene glycol (e.g., PEG 100, PEG 300, PEG 400and PEG 3350), diethylene glycol monoethyl ether, polysorbates (e.g.,Tween® 20 to 80), Labrasol®, fatty acid esters (e.g., isopropylmyristate and diisopropyl adipate), diethyl sebacate, propylene glycolmonocaprylate, propylene glycol laurate, mono- and di-glycerides (e.g.,Capmul® MCM), medium-chain triglycerides, caprylic/capric triglyceride,glyceryl monocaprylate, glyceryl mono-oleate, glyceryl mono-linoleate,glycerol oleate/propylene glycol, mineral oil, and vegetable oils.

A liphophilic solvent may also function as a formulation base orcarrier. For example, polyethylene glycol (e.g., from PEG 100 to PEG3500, such as PEG 300, PEG 400 and PEG 3350) can function as aliphophilic solvent and a formulation base.

The composition can also contain a hydrophilic solvent, such as a C₁-C₅alcohol (e.g., ethanol, isopropanol, glycerol, propylene glycol and1,2-pentanediol) and/or water.

The composition can contain a thickener to increase the viscosity and/orthe physical stability of the composition. Examples of thickenersinclude without limitation glycerol, stearyl alcohol, and polymers(e.g., polydimethylsiloxane [dimethicone] and Carbopol® polymers).

In some embodiments, the composition further contains an antioxidant.Non-limiting examples of antioxidants include butylated hydroxyanisole(BHA), butylated hydroxytoluene (BHT), tocopherols (e.g., Vitamin E andesters thereof), flavinoids, glutathione, ascorbic acid and estersthereof, DMSO, and chelating agents (e.g., EDTA and citric acid).

In certain embodiments, the topical composition comprises on a w/w basisabout 0.1-5% or 0.5-5% of a treprostinil derivative, about 2-30% or5-20% of a permeation enhancer, about 20-80% or 30-70% of a lipophilicsolvent that may also function as a formulation base, about 0.1-10% or1-7.5% of a thickener, and about 0.01-2% or 0.05-1% of an antioxidant.As a non-limiting example, a topical composition can contain atreprostinil derivative, PEG 400 and/or PEG 3350 as lipophilicsolvent(s) and formulation base(s), diethylene glycol monoethyl ether,oleyl alcohol and/or isopropyl myristate as permeation enhancer(s),stearyl alcohol as a thickener, and BHT as an antioxidant.

The topical composition can have any suitable dosage form, such as acream, a lotion, a gel, an ointment, a jelly, a paste, or anytransdermal device (e.g., a patch) that administers a drug by absorptionthrough the skin or mucosa.

Topical Compositions Comprising a Permeation Enhancer and an Adhesive

In additional embodiments, a topical composition comprises atreprostinil derivative, a permeation enhancer and an adhesive. Thecomposition can optionally contain an additional therapeutic agent.

The permeation enhancer increases the permeability of the skin or mucosato the therapeutic agent(s). The permeation enhancer can be, e.g., afatty acid ester having a fatty acyl chain length of C₈-C₂₀ or C₁₂-C₁₈and a C₁-C₆ or C₂-C₄ alcohol component (e.g., isopropanol). In certainembodiments, the permeation enhancer is isopropyl myristate or isopropylpalmitate. In some embodiments, the permeation enhancer is in an amountof about 0.1-20%, 0.5-15%, 1-15%, 2-12% or 4-10% by weight of thecomposition or the skin-contacting layer of a transdermal patch.

The adhesive maintains contact of the topical composition to the skin ormucosa. Non-limiting examples of adhesives include acrylics/acrylates(e.g., polyacrylates, including polyalkyl acrylates and Duro-Tak®polyacrylates), polyvinyl acetate, ethylenevinylacetate copolymers,polysiloxanes, polyurethanes, plasticized polyether block amidecopolymers, natural and synthetic rubbers, plasticized styrene-butadienerubber block copolymers (e.g., Duro-Tak® 87-6173), and mixtures thereof.

The topical composition can comprise one or more additional excipients.The additional excipient(s) can be, e.g., a diluent, an emollient, aplasticizer, or an agent that reduces irritation to the skin or mucosa,or a combination thereof.

In certain embodiments, the topical composition prior to application tothe skin or mucosa is substantially free of water, tetraglycol(glycofurol) and/or a hydrophilic organic solvent (e.g., a C₁-C₅alcohol).

The composition can administer the therapeutic agent(s) transdermally(including percutaneously and transmucosally) through a body surface ormembrane such as intact unbroken skin or intact unbroken mucosal tissueinto the systemic circulation.

In some embodiments, the topical composition is in the form of atransdermal patch for application to the skin or mucosa. The patch has askin- or mucosa-contacting layer (“skin-contacting layer” forsimplicity) laminated or otherwise attached to a support layer. Theskin-contacting layer can be covered by a removable release liner beforeuse to protect the skin-contacting surface and to keep it clean until itis applied to the skin or mucosa. The support layer of the patch acts asa support for the skin-contacting layer and as a barrier that preventsloss of the therapeutic agent(s) in the skin-contacting layer to theenvironment. The material of the support layer is compatible with thetherapeutic agent(s), the permeation enhancer and the adhesive, and isminimally permeable to the components of the patch. The support layercan be opaque to protect the components of the patch from degradationvia exposure to ultraviolet light. The support layer is also capable ofbinding to and supporting the adhesive layer, yet is sufficientlypliable to accommodate the movements of the subject using the patch. Thematerial of the support layer can be, e.g., a metal foil, a metalizedpolyfoil, or a composite foil or film containing a polymer (e.g., apolyester [such as polyester terephthalate] or aluminized polyester,polyethylene, polypropylene, polytetrafluoroethylene, a polyethylenemethyl methacrylate block copolymer, a polyether block amide copolymer,a polyurethane, polyvinylidene chloride, nylon, a silicone elastomer,rubber-based polyisobutylene, styrene, or a styrene-butadiene orstyrene-isoprene copolymer). The release liner can be made of the samematerial as the support layer, or can be a film coated with anappropriate release surface.

Therapeutic Uses of Treprostinil Derivatives

In some embodiments, the compounds described herein are used to treatpulmonary hypertension. Accordingly, the disclosure provides a method oftreating pulmonary hypertension, comprising administering to a subjectin need of treatment a therapeutically effective amount of atreprostinil derivative, or a pharmaceutically acceptable salt, solvate,clathrate or polymorph thereof. Treprostinil derivatives includeprodrugs of treprostinil. An additional therapeutic agent can optionallybe administered to treat pulmonary hypertension.

Pulmonary hypertension is an increase of blood pressure in the lungvasculature, including the pulmonary artery, pulmonary vein andpulmonary capillaries. Thus, pulmonary hypertension encompassespulmonary arterial hypertension (PAH) and pulmonary venous hypertension(PVH) (e.g., congestive heart failure). More broadly, pulmonaryhypertension encompasses:

WHO Group I—pulmonary arterial hypertension, including idiopathic PAH,heritable PAH (e.g., BMPR2, ALK1 and endoglin [with or withouthereditary hemorrhagic telangiectasia]), drug- and toxin-induced PAH,PAH associated with various conditions (e.g., connective tissue disease,HIV infection, portal hypertension, congenital heart disease,schistosomiasis, and chronic hemolytic anemia [e.g., sickle celldisease]), persistent pulmonary hypertension of the newborn, pulmonaryveno-occlusive disease (PVOD), and pulmonary capillary hemangiomatosis(PCH);

WHO Group II—pulmonary hypertension owing to left heart disease,including systolic dysfunction, diastolic dysfunction and valvular heartdisease;

WHO Group III—pulmonary hypertension owing to lung disease and/orhypoxia, including chronic obstructive pulmonary disease (COPD),interstitial lung disease, other pulmonary diseases with mixedrestrictive and obstructive pattern, sleep-disordered breathing,alveolar hypoventilation disorders, chronic exposure to high altitude,and developmental abnormalities;

WHO Group IV—chronic thromboembolic pulmonary hypertension (CTEPH); and

WHO Group V—pulmonary hypertension with unclear multifactorialmechanisms, including hematologic diseases (e.g., myeloproliferativedisease and splenectomy), systemic diseases (e.g., sarcoidosis,pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis,neurofibromatosis and vasculitis), metabolic disorders (e.g., glycogenstorage disease, Gaucher disease and thyroid diseases), and other causes(e.g., tumoral obstruction, fibrosing mediastinitis, and chronic renalfailure on dialysis).

The therapeutically effective amount and frequency of administration ofa treprostinil derivative to treat pulmonary hypertension may depend onvarious factors, including the type of pulmonary hypertension, theseverity of the condition, the mode of administration, the age, bodyweight, general health, gender and diet of the subject, and the responseof the subject to the treatment, and can be determined by the treatingphysician. In certain embodiments, the effective dose of a treprostinilderivative per day is about 0.1-100 mg, 0.1-50 mg, 0.5-50 mg, 0.5-25 mg,0.5-10 mg, 1-10 mg or 1-5 mg, or as deemed appropriate by the treatingphysician, which can be administered in a single dose or in divideddoses. In further embodiments, the effective dose of a treprostinilderivative per day is about 0.001-2 mg/kg, 0.005-1 mg/kg, 0.01-0.5 mg/kgor 0.01-0.1 mg/kg body weight, or as deemed appropriate by the treatingphysician.

In some embodiments, a treprostinil derivative is administered, in asingle dose or in multiple doses, daily (including one, two, three ormore times daily), every two days, every three days, twice weekly,thrice weekly, weekly, every 2 weeks, every 3 weeks, monthly, every 6weeks, every 2 months or every 3 months, or as deemed appropriate by thetreating physician. In further embodiments, a treprostinil derivative isadministered under a chronic dosing regimen. In certain embodiments, atherapeutically effective amount of a treprostinil derivative isadministered over a period of at least 2 weeks, 3 weeks, 1 month, 1.5months, 2 months, 3 months, 4 months, 5 months, 6 months or longer.

A treprostinil derivative can be administered via any suitable route.Potential routes of administration of a treprostinil derivative includewithout limitation oral, parenteral (including intramuscular,subcutaneous, intradermal, intravascular, intravenous, intraarterial,intramedullary and intrathecal), intraperitoneal, and topical (includingdermal/epicutaneous, transdermal, mucosal, transmucosal, intranasal[e.g., by nasal spray or drop], intraocular [e.g., by eye drop],pulmonary [e.g., by inhalation], buccal, sublingual, rectal andvaginal). In certain embodiments, a treprostinil derivative isadministered orally. In other, embodiments, a treprostinil derivative isadministered topically (e.g. dermally, transdermally, mucosally,transmucosally, intranasally, pulmonarily [e.g., by inhalation], orsublingually). In further embodiments, a treprostinil derivative isadministered parenterally (e.g., subcutaneously or intravenously,including by injection or infusion).

In some embodiments, a treprostinil derivative is used to treat PAH. Infurther embodiments, an additional therapeutic agent is administered incombination with the treprostinil derivative to treat PAH. Theadditional therapeutic agent can be administered concurrently with orsequentially to (before or after) administration of the treprostinilderivative. If administered concurrently with the treprostinilderivative, the additional therapeutic agent can be contained in thesame composition as the treprostinil derivative or in separatecompositions.

In certain embodiments, the additional therapeutic agent for thetreatment of PAH is selected from the group consisting of:

vasoactive agents, including without limitation prostaglandins andprostanoids (e.g., prostacyclin [prostaglandin I₂] and beraprost),endothelin receptor (e.g., ET_(A) and/or ET_(B)) antagonists (e.g.,ambrisentan, bosentan, sitaxentan and Actelion-I), phosphodiesterasetype 5 (PDE5) inhibitors (e.g., sildenafil and tadalafil), activators ofsoluble guanylate cyclase (e.g., cinaciguat and riociguat), and analogsand derivatives thereof;

diuretics, including without limitation thiazide diuretics (e.g.,bendroflumethiazide, chlorothiazide, epitizide and hydrochlorothiazide),thiazide-like diuretics (e.g., chlorthalidone, indapamide andmetolazone), and analogs and derivatives thereof;

anticoagulants, including without limitation vitamin K antagonists(e.g., acenocoumarol, atromentin, coumarin, phenindione, phenprocoumonand warfarin), direct thrombin inhibitors (e.g., argatroban, dabigatran,hirudin, lepirudin and bivalirudin), direct factor Xa inhibitors (e.g.,apixaban, betrixaban, darexaban, edoxaban, eribaxaban, letaxaban andrivaroxaban), heparin and derivatives thereof (e.g., unfractionatedheparin, low molecular weight heparin, fondaparinux and idraparinux),others (e.g., antithrombin, batroxobin and hementin), and analogs,derivatives and fragments thereof; and

other kinds of therapeutic agents, including without limitation cardiacglycosides (e.g., digoxin, acetyldigoxin and digoxigenin) and oxygentherapy.

EXAMPLES

Additional embodiments are provided in the following, non-limitingexamples.

Four assays on compounds were carried out by the following methods withthe results shown in Table I.

(Test 1) Human liver microsomal stability assay was conducted byincubating 0.5 uM test compounds at 37° C. for up to 45 minutes in 50 mMof potassium phosphate buffer (pH 7.4) containing 0.5 mg of microsomalprotein and 50 μL of NADPH generating system (7.8 mg of glucose6-phosphate, 1.7 mg of NADPH and 6 U of glucose 6-phosphatedehydrogenase per mL in 2% w/v of sodium bicarbonate). At 0, 5, 15, 30and 45 min., an aliquot was taken, quenched with internal standardcontaining stop solution. No co-factor controls at 45 minutes were alsoprepared. After incubation, the samples were analyzed by LC-MS/MS. Peakarea ratios of analyte to internal standard were used to calculate theintrinsic clearance. The intrinsic clearance (CL_(int)) was determinedfrom the first order elimination constant by non-linear regression.Formation of the active drug Compound A over the time course was alsomonitored by LC-MS/MS analysis.

(Test 2) Human plasma stability assay was conducted by incubating 0.5 uMtest compounds at 37° C. for up to 120 minutes in heparinated humanplasma. At 0, 5, 15, 30, 60 and 120 and 240 min., an aliquot was taken,quenched with internal standard containing stop solution. Afterincubation, the samples were analyzed by LC-MS/MS. Peak area ratios ofanalyte to internal standard were used to calculate the half-life.Formation of the active drug Compound A over the time course was alsomonitored by LC-MS/MS analysis.

(Test 3) Human skin homogenate stability assay was conducted in asimilar way as the human liver microsomal stability assay, by incubating0.5 uM test compounds at 37° C. for up to 45 minutes in 50 mM ofpotassium phosphate buffer (pH 7.4) containing 0.5 mg of human skinhomogenate protein and 50 μL of NADPH generating system (7.8 mg ofglucose 6-phosphate, 1.7 mg of NADPH and 6 U of glucose 6-phosphatedehydrogenase per mL in 2% w/v of sodium bicarbonate). At 0, 5, 15, 30and 45 min., an aliquot was taken, quenched with internal standardcontaining stop solution. No co-factor controls at 45 minutes were alsoprepared. After incubation, the samples were analyzed by LC-MS/MS. Peakarea ratios of analyte to internal standard were used to calculate theintrinsic clearance. The intrinsic clearance (CL_(int)) was determinedfrom the first order elimination constant by non-linear regression.Formation of the active drug Compound A over the time course was alsomonitored by LC-MS/MS analysis.

(Test 4) Human hepatocyte stability assay was conducted by incubating0.5 uM test compound at 37° C. for up to 240 minutes. Cryopreservedhuman hepatocytes were obtained from Celsis IVT (Baltimore, Md.). Cellswere thawed according to vendor's instructions and were suspended inWilliam's Medium E to 0.5 million cells/mL. Test compounds were spikedinto the cell suspension to initiate the reactions. At 0, 10, 30, 60,120 and 240 min., an aliquot was taken, quenched with internal standardcontaining stop solution. After incubation, the samples were analyzed byLC-MS/MS. Peak area ratios of analyte to internal standard were used tocalculate the intrinsic clearance. The intrinsic clearance (CL_(int))was determined from the first order elimination constant by non-linearregression. Formation of the active drug Compound A over the time coursewas also monitored by LC-MS/MS analysis.

Assay results (half life) are shown in Table I. In Table I, the code forthe results of the assay testing is:

A=<15 min

B=15-30 min

C=31-60 min

D=>60 min

TABLE I Compd MW m/z Test 1 Test 2 Test 3 Test 4 No. (g/mol) [M + Na]+T_(1/2) T_(1/2) T_(1/2) T_(1/2) A 390 413 1 444.62 467.62 A A 2 443.63466.63 A D C 3 503.68 526.68 4 450.6 473.6 A A 5 460.62 483.62 A A 6476.62 499.62 A A 7 433.59 456.59 B D B 8 432.61 455.61 C 9 434 457 A 10448 471 A 11 447 470 A D 12 461 484 A D 13 475 498 A D A 14 471 494 A DD A 15 404 427 A A A 16 460 483 A B B 17 460 483 A C B 18 474 497 A D D19 484 507 A C B 20 432 455 A C A 21 521 544 A D 22 488 511 A D D 23 488511 A D 24 472 495 A D 25 476 499 A D C 26 446 489 A B B 27 532 555 A D28 446 469 A B 57 372 395 D D D 60 446 A C C 61 446 A B C 62 460 A C D63 460 A C C 64 502 A D D

Compounds 60 to 64 have the structure shown below:

Examples of Synthesis of Treprostinil Derivatives

The following representative syntheses are shown for compounds accordingto Formulae I, II, and III.

Example 1 Synthesis of2-[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-N-(2,2,2-trifluoro-ethyl)-acetamide

A solution of{2-Hydroxy-1-[3-(tetrahydro-pyran-2-yloxy)-octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy}-aceticacid (94 mg, 0.2 mmol), trifluoroethylamine (54 mg, 0.6 mmol) and DIPEA(104 μl, 0.6 mmol) in DMF (2 ml) was treated with HATU and stirred 24 hrat RT. The reaction mixture was diluted with MTBE and washed withsaturated sodium bicarbonate solution and brine, dried over sodiumsulfate and concentrated under vacuum. The residue was purified bysilica gel chromatography. This resulting material was dissolved in MeOH(4 ml), treated with Amberlite IR120H and stirred 24 hr. The reactionmixture was filtered and concentrated to yield2-[2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-N-(2,2,2-trifluoro-ethyl)-acetamide(46 mg) as an oil. ¹HNMR (400 MHz, CDCl₃) δ 7.06 (d, 1H, J=7.6); 6.80(d, 1H, J=7.2); 6.63 (d, 1H, J=8.0); 4.86 (quint., 1H, J=6.4); 4.60 (s,2H); 3.7-3.8 (m, 1H); 3.55-3.65 (m, 1H); 2.85-2.95 (ddd, 1H); 2.70-2.80(dd, 1H); 2.50-2.60 (ddd, 1H); 2.40-2.50 (dd, 1H); 2.15-2.3 (m, 2H);1.75-1.95 (m, 2H); 1.24-1.70 (m, 17H); 1.20 (d, 3H, J=6.4); 0.85-0.95(m, 8H); MS: m/z 494 [M+Na]⁺

Example 2 Synthesis of[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 1,2-dimethyl-propyl ester

A solution of{2-Hydroxy-1-[3-(tetrahydro-pyran-2-yloxy)-octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy}-aceticacid (47 mg, 0.1 mmol), 3-methyl-2-butanol (26 mg, 0.3 mmol) and DMAP(12 mg, 0.1 mmol) in DCM (1 ml) was treated with EDC (26 mg, 0.14 mmol)and stirred 24 hr at RT. The reaction mixture was diluted with MTBE andwashed with saturated sodium bicarbonate solution and brine, dried oversodium sulfate and concentrated under vacuum. The residue was purifiedby silica gel chromatography. This resulting material was dissolved inMeOH/THF (4 ml), treated with Amberlite IR120H and stirred 24 hr. Thereaction mixture was filtered and concentrated to yield[2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid 1,2-dimethyl-propyl ester (16 mg) as an oil. ¹HNMR (400 MHz, CDCl₃)δ 7.06 (d, 1H, J=7.6); 6.80 (d, 1H, J=7.2); 6.63 (d, 1H, J=8.0); 4.86(quint., 1H, J=5.6); 4.60 (s, 2H); 3.7-3.8 (m, 1H); 3.55-3.80 (m, 1H);3.55-3.70 (m, 1H); 2.85-2.95 (dd, 1H); 2.50-2.80 (dd, 1H); 2.50-2.60(dd, 1H); 2.40-2.60 (dd, 1H); 2.15-2.30 (m, 2H); 1.75-1.95 (m, 2H);1.35-1.80 (m, 17H); 1.19 (d, 3H, J=6.4); 0.85-0.95 (m, 8H); MS: m/z 483[M+Na]⁺

Example 3 Synthesis of: treprostinil 2-hydroxy lactone

A solution of{2-Hydroxy-1-[3-(tetrahydro-pyran-2-yloxy)-octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy}-aceticacid (47 mg, 0.1 mmol) and DMAP (26 mg, 0.2 mmol) in DCM (1 ml) wastreated with 2,4,6-trichlorobenzoyl chloride (27 mg, 0.11 mmol) andstirred 24 hr at RT. The reaction mixture was diluted with ethyl acetateand washed with saturated sodium bicarbonate solution and brine, driedover sodium sulfate and concentrated under vacuum. The residue waspurified by silica gel chromatography. This resulting material wasdissolved in MeOH/THF (4 ml), treated with Amberlite IR120H and stirred24 hr. The reaction mixture was filtered and concentrated to yieldtreprostinil 2-hydroxy lactone (8 mg) as an oil. ¹HNMR (400 MHz, CDCl₃)δ 7.03 (dd, 1H, J=8.4 Hz, J=7.6 Hz); 6.74 (d, 1H, J=7.6 Hz); 6.55 (d,1H, J=8.4 Hz) 4.53 (m, 1H); 4.46 (d, 1H, J=15.2 Hz); 4.31 (d, 1H, J=15.2Hz); 3.53 (m, 1H); 2.5 (m, 1H); 2.8 (dd, 1H); 2.6 (dd, 1H); 2.2-2.55 (m,4H); 1.53 (m, 4H); 1.35-1.47 (m, 4H); 1.3 (m, 6H); 0.89 (m, 3H); MS: m/z395 [M+Na]⁺

Example 4 Synthesis of Cyclopropanecarboxylic acid1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ylester

A solution of[2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-aceticacid methyl ester (32 mg, 0.06 mmol), DIPEA (31 μl, 0.18 mmol) and DMAP(1 crystal) in DCM (2 ml) was treated with cyclopropanecarbonyl chloride(8 μl, 0.08 mmol) and stirred for 24 hr at RT under nitrogen. Thereaction mixture was diluted with MTBE and washed with saturated sodiumbicarbonate solution and brine, dried over sodium sulfate andconcentrated under vacuum. The residue was purified by silica gelchromatography. This resulting material was dissolved in MeOH/THF (4ml), treated with Amberlite IR120H and stirred 24 hr. The reactionmixture was filtered and concentrated to yield cyclopropanecarboxylicacid1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ylester (32 mg) as an oil. ¹HNMR: (400 MHz, DMSO-d₆) δ 7.06 (d, 1H,J=7.6); 6.80 (d, 1H, J=7.2); 6.63 (d, 1H, J=8.8); 4.78 (s, 2H); 4.1-4.2(m, 1H); 4.05-4.50 (m, 1H); 3.68 (s, 3H); 2.6-2.8 (m, 2H); 2.4-2.5 (m,2H); 2.20-2.35 (m, 1H); 2.10-2.20 (m,1H); 1.8-1.95 (m, 1H); 1.10-1.16(m, 15H); 0.95-1.10 (m, 1H); 0.70-0.90 (m, 7H); MS: m/z 495 [M+Na]⁺

Example 5 Synthesis of Formula III Compound

A solution of acrylic acid1-[2-(2-acryloyloxy-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-ethyl]-hexylester (51 mg, 0.1 mmol) in chloroform (20 ml) is treated with a solutionof (PCy3)2Cl2Ru=CHPh (19 mg, 0.023 mmol) in chloroform (3 ml) andstirred 24 hr at RT. TEA (1 ml) is added and the solution isconcentrated under vacuum. The residue is purified by silica gelchromatography to yield the title compound.

Additional synthetic schemes are shown below:

Example 6 Formula I Compound

Example 7 Formula I Compound

1-57. (canceled)
 58. A compound represented by Formula III:

wherein: L₂ is selected from the group consisting of:

wherein, m is 1, 2, 3, or 4; X is NR₁₄, or O; R₁₄ is selected from thegroup consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl,heteroalkyl, substituted alkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, substituted aryl, substituted heteroaryl, substitutedarylalkyl, and substituted heteroarylalkyl; and R₁₆ and R₁₇ areindependently in each occurrence H or alkyl, or R₁₆ and R₁₇ takentogether with the atom to which they are attached optionally form a 3-to 6-membered ring; R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉,R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are independently H and ordeuterium; Z is —OH, —OR₁₁, —N(R₁₁)R₁₂, —SR₁₁, or P₁, wherein: R₁₁ isalkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, haloalkyl,heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, alkylcycloalkyl, substituted alkylcycloalkyl,alkylcycloheteroalkyl, substituted alkylcycloheteroalkyl, aryl,substituted aryl, alkylaryl, substituted alkylaryl, heteroaryl,substituted heteroaryl, alkylheteroaryl, or substituted alkylheteroaryl;R₁₂ is H, haloalkyl, heteroalkyl, cycloheteroalkyl, alkylcycloalkyl,alkylcycloheteroalkyl, aryl, or heteroaryl; and P₁ is selected from thegroup consisting of:

wherein, m is 1, 2, 3, or 4; R₁₄ and R₁₅ are independently in eachoccurrence selected from the group consisting of H, alkyl, cycloalkyl,alkylcycloalkyl, haloalkyl, heteroalkyl, substituted alkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, substituted aryl, substitutedheteroaryl, substituted arylalkyl, and substituted heteroarylalkyl; orR₁₄ and R₁₅ taken together with the atoms to which they are attachedoptionally form a 5- to 7-membered ring which is unsubstituted orsubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halo, methyl, and methoxy; R₁₈ and R₁₉ areindependently in each occurrence hydrogen or alkyl, wherein the alkyl isunsubstituted or substituted with 1 substituent selected from the groupconsisting of halo, hydroxy, alkoxy, amino, thio, methylthio, —C(O)OH,—C(O)O-(alkyl), —CONH₂, aryl, and heteroaryl, wherein the aryl andheteroaryl are unsubstituted or substituted with a substituent selectedfrom the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy,and haloalkoxy; R₁₄ and R₁₈ taken together with the atoms to which theyare attached optionally form a 5- to 7-membered ring; R₁₄ and R₁₉ takentogether with the atoms to which they are attached optionally form a 5-to 7-membered ring; R₁₅ and R₁₈ taken together with the atoms to whichthey are attached optionally form a 5- to 7-membered ring; and R₁₅ andR₁₉ taken together with the atoms to which they are attached optionallyform a 5- to 7-membered ring; or an enantiomer, pharmaceuticallyacceptable salt or polymorph thereof.
 59. The compound of claim 58,wherein L₂ is selected from the group consisting of:


60. The compound of claim 58, wherein R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆,R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are H.
 61. Thecompound of claim 58, wherein at least one of R₂₀, R₂₁, R₂₂, R₂₃, R₂₄,R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ isdeuterium.
 62. (canceled)
 63. A compound having Formula III(AA):

wherein, R₀₁₁ is haloalkyl, heteroalkyl, cycloheteroalkyl,alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl; R₀₃, R₀₄,R₀₅, R₀₆, R₀₇ and R₀₈ are independently H or deuterium; X is O, NR₀₁₂,or S, wherein R₀₁₂ is haloalkyl, heteroalkyl, cycloheteroalkyl,alkylcycloalkyl, alkylcycloheteroalkyl, aryl, or heteroaryl; and Y isC═O, or an enantiomer, pharmaceutically acceptable salt or polymorphthereof.
 64. (canceled)
 65. (canceled)
 66. A composition comprising acompound of claim 58 or a pharmaceutically acceptable salt thereof andone or more pharmaceutically acceptable carriers or excipients.
 67. Thecomposition of claim 66, which is formulated for transdermal delivery.68. The composition of claim 66, which is formulated for transdermaldelivery with a patch. 69-72. (canceled)
 73. A method of treatingpulmonary hypertension, comprising administering to a subject in need oftreatment a therapeutically effective amount of a compound of claim 58or a pharmaceutically acceptable salt thereof.
 74. (canceled) 75.(canceled)
 76. The method of claim 73, wherein the compound isadministered orally, topically or parenterally.
 77. The method of claim76, wherein the compound is administered transdermally.
 78. The methodof claim 73, wherein the pulmonary hypertension is pulmonary arterialhypertension.
 79. The method of claim 73, further comprisingadministering an additional therapeutic agent.
 80. The method of claim79, wherein the additional therapeutic agent is selected from the groupconsisting of vasoactive agents, diuretics, cardiac glycosides andanticoagulants.
 81. (canceled)
 82. The method of claim 77, wherein thecompound is administered via a transdermal patch.